JP4955566B2 - Fused heterocyclic derivative, pharmaceutical composition containing the same, and pharmaceutical use thereof - Google Patents

Description

  The present invention relates to a fused heterocyclic derivative.

  More specifically, the present invention has gonadotropin-releasing hormone antagonistic action, and is prostatic hypertrophy, uterine fibroid, endometriosis, uterine fibroma, precocious puberty, amenorrhea, premenstrual syndrome, menstruation A fused heterocyclic derivative or a prodrug thereof, a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof, which can be used for a prophylactic or therapeutic agent for sex hormone-dependent diseases such as difficulty, and the like, and The present invention relates to a pharmaceutical composition containing the same.

  Gonadotropin Releasing Hormone (GnRH or GnRH is also called luteinizing hormone releasing hormone Luteinizing Hormone Releasing Hormone: LHRH, hereinafter referred to as “GnRH”) is a peptide consisting of 10 amino acids secreted from the hypothalamus. (PGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2). GnRH secreted into the pituitary portal vein is a gonadotropin hormone (Luteinizing Hormone: LH, follicular follicle) via a receptor thought to be present in the anterior pituitary gland (GnRH receptor). Promotes production and secretion of stimulating hormone (Follicle Stimulating Hormone: FSH). These gonadotropins act on the gonads (ovary, testis) to promote follicular development, ovulation, luteinization and spermatogenesis, while promoting production and secretion of sex hormones (estrogens, progesterone, androgens) (non-patented) Reference 1). Therefore, this specific and selective antagonist for the GnRH receptor is expected as a prophylactic / therapeutic agent for sex hormone-dependent diseases because it regulates the action of GnRH and regulates the production and secretion of gonadotropins and sex hormones. The

  GnRH receptor superagonists are used as therapeutic agents for sex hormone-dependent diseases such as prostate cancer, breast cancer and endometriosis as drugs that suppress the function of GnRH receptors. GnRH receptor superagonist binds to GnRH receptor, and after a transient gonadotropin secretion stimulating action (flare-up phenomenon) at the beginning of administration, depletion of gonadotropin and down-regulation of GnRH receptor It suppresses its function by causing. Therefore, the GnRH receptor superagonist has a problem that its disease state is temporarily worsened based on the increased secretion of gonadotropin at the initial stage of administration. On the other hand, GnRH receptor antagonists (hereinafter referred to as “GnRH antagonists”) exhibit a suppressive action without gonadotropin secretion because their mechanism of inhibition is binding inhibition to the GnRH receptor. It is expected. In recent years, peptide GnRH antagonists such as abarelix and cetrorelix have been developed as GnRH antagonists, and are used for the treatment of prostate cancer, infertility and the like. However, these peptidic GnRH antagonists are difficult to absorb orally and therefore have to be administered subcutaneously or intramuscularly, and it is expected to avoid local reactivity at the injection site and flexible dosage control. The development of an administrable non-peptide GnRH antagonist is awaited (see Non-Patent Document 2).

  As condensed pyrimidine derivatives having a non-peptide GnRH antagonistic action, compounds described in Patent Documents 1 and 2 are known. However, all of the compounds described in Patent Document 1 have an aryl substituent on a 5-membered heterocyclic ring condensed with a pyrimidine ring. Moreover, the compound described in Patent Document 2 is a pyrimidine derivative condensed with an aromatic 6-membered ring and does not necessarily have high oral absorbability. Recently published Patent Document 3 discloses a pyrimidine derivative having a non-peptide GnRH antagonistic action condensed with a 5-membered hetero ring. However, there is no specific description of compounds other than sulfonamide or compounds having an amide group, and there is no specific description of blood kinetics in oral administration.

As a compound having a pyrimidine ring condensed with a 5-membered hetero ring, Patent Document 4 discloses a serine protease inhibitor, Patent Document 5 discloses a blood coagulation factor Xa inhibitor, Patent Document 6 discloses Various compounds are listed as herbicides and the like. However, these documents neither describe nor suggest that a compound having a pyrimidine ring condensed with a 5-membered hetero ring of the present invention has a GnRH antagonistic action.
“Standard Physiology”, 5th edition, Medical School, pp. 882-891 “Obstetrics and gynecology”, 2004, Vol. 71, No. 3, pp. 280-285, 301-307 International Publication No. 1996/24597 Pamphlet International Publication No. 2005/019188 Pamphlet International Publication No. 2006/083005 Pamphlet US Patent Application Publication No. 2003/0004167 International Publication No. 00/39131 Pamphlet Japanese Patent Publication No. 6-510992

  An object of the present invention is to provide a compound having a GnRH antagonistic action.

  As a result of intensive studies to solve the above problems, the present inventors have found that a pyrimidine derivative condensed with a 5-membered heterocycle represented by the following general formula (I) has an excellent GnRH antagonistic activity, The present inventors have found for the first time that blood kinetics are superior in oral administration compared to pyrimidine derivatives condensed with a family 6-membered ring, and have completed the present invention.

〔式中、
環Ａは、５員環不飽和炭化水素又は５員環へテロアリール；
Ｒ^Ａは、ハロゲン原子、シアノ基、ニトロ基、置換可低級アルキル基、置換可低級アルケニル基、置換可低級アルキニル基、ヒドロキシイミノメチル基、置換可低級アルキルスルホニル基、置換可低級アルキルスルフィニル基、テトラゾリル基、ＯＷ^１、ＳＷ^１、ＣＯＷ^１、ＣＯＯＷ^１、ＮＨＣＯＷ^１、ＮＨＣＯＮＷ^２Ｗ^３、ＮＷ^２Ｗ^３、ＣＯＮＷ^２Ｗ^３又はＳＯ_２ＮＷ^２Ｗ^３（Ｗ^１〜Ｗ^３は、独立して、水素原子又は置換可低級アルキル基であるか、Ｗ^２及びＷ^３は両者が結合して隣接する窒素原子とともに置換可環状アミノ基を形成してもよい）；
ｍは、０〜３の整数；
環Ｂはアリール又はヘテロアリール；
Ｒ^Ｂは、ハロゲン原子、シアノ基、置換可低級アルキル基、ＯＷ^４、ＣＯＷ^４、ＣＯＯＷ^４又はＣＯＮＷ^５Ｗ^６（Ｗ^４〜Ｗ^６は、独立して、水素原子又は置換可低級アルキル基であるか、Ｗ^５及びＷ^６は両者が結合して隣接する窒素原子とともに置換可環状アミノ基を形成してもよい）；
ｎは、０〜２の整数；
Ｅ^１は、酸素原子、硫黄原子又はＮ−ＣＮ；
Ｅ^２は、酸素原子又はＮＨ；
Ｕは、単結合又は置換可低級アルキレン基；
Ｘは、Ｙ、−ＣＯ−Ｙ、−ＳＯ_２−Ｙ、−Ｓ−Ｌ−Ｙ、−Ｏ−Ｌ−Ｙ、−ＣＯ−Ｌ−Ｙ、−ＣＯＯ−Ｌ−Ｙ、−ＳＯ−Ｌ−Ｙ、−ＳＯ_２−Ｌ−Ｙ、−Ｓ−Ｚ、−Ｏ−Ｚ又は−ＣＯＯ−Ｚで表される基
（式中、Ｌは、置換可低級アルキレン基；
Ｙは、Ｚ又は−ＮＷ^７Ｗ^８〔Ｗ^７及びＷ^８は、独立して、水素原子、置換可低級アルキル基又はＺであるか（但し、同時に水素原子ではない）、Ｗ^７及びＷ^８は両者が結合して隣接する窒素原子とともに置換可環状アミノ基を形成してもよい〕で表される基；
Ｚは、縮環していてもよい置換可シクロアルキル基、縮環していてもよい置換可ヘテロシクロアルキル基、縮環していてもよい置換可アリール基又は縮環していてもよい置換可ヘテロアリール基；である）；である〕
で表される縮合複素環誘導体もしくはそのプロドラッグ又はその薬理学的に許容される塩、又はその水和物もしくは溶媒和物；
〔２〕 環Ａが、５員環ヘテロアリール環である、前記〔１〕記載の縮合複素環誘導体もしくはそのプロドラッグ又はその薬理学的に許容される塩、又はその水和物もしくは溶媒和物；
〔３〕 環Ａの５員環ヘテロアリール環が、式

で表されるチオフェン環のいずれかである、前記〔２〕記載の縮合複素環誘導体もしくはそのプロドラッグ又はその薬理学的に許容される塩、又はその水和物もしくは溶媒和物；That is, the present invention
[1] General formula (I):

[Where,
Ring A is a 5-membered unsaturated hydrocarbon or 5-membered heteroaryl;
R ^A is a halogen atom, cyano group, nitro group, substitutable lower alkyl group, substitutable lower alkenyl group, substitutable lower alkynyl group, hydroxyiminomethyl group, substitutable lower alkylsulfonyl group, substitutable lower alkylsulfinyl group, Tetrazolyl group, OW ¹ , SW ¹ , COW ¹ , COOW ¹ , NHCOW ¹ , NHCONW ² W ³ , NW ² W ³ , CONW ² W ³ or SO ₂ NW ² W ³ (W ^{1 to} W ³ are independently , A hydrogen atom or a substituted lower alkyl group, or W ² and W ³ may be bonded together to form a substituted cyclic amino group together with the adjacent nitrogen atom);
m is an integer of 0 to 3;
Ring B is aryl or heteroaryl;
R ^B represents a halogen atom, a cyano group, a substitutable lower alkyl group, OW ⁴ , COW ⁴ , COOW ⁴ or CONW ⁵ W ⁶ (W ^{4 to} W ⁶ are independently a hydrogen atom or a substitutable lower alkyl group. Or W ⁵ and W ⁶ may combine together to form a substituted cyclic amino group with the adjacent nitrogen atom);
n is an integer of 0 to 2;
E ¹ represents an oxygen atom, a sulfur atom or N-CN;
E ² represents an oxygen atom or NH;
U represents a single bond or a substitutable lower alkylene group;
X _{is, Y, -CO-Y, -SO} 2 -Y, -S-L-Y, -O-L-Y, -CO-L-Y, -COO-L-Y, -SO-L-Y , -SO ₂ -LY, -SZ, -OZ or -COO-Z (wherein L is a substitutable lower alkylene group;
Y is Z or —NW ⁷ W ⁸ [W ⁷ and W ⁸ are independently a hydrogen atom, a substitutable lower alkyl group or Z (however, they are not simultaneously a hydrogen atom), or W ⁷ and W ^8. May combine to form a substituted cyclic amino group together with the adjacent nitrogen atom];
Z is a substituted cycloalkyl group that may be condensed, a substituted heterocycloalkyl group that may be condensed, a substituted aryl group that may be condensed, or a substituent that may be condensed. A heteroheteroaryl group;
A fused heterocyclic derivative represented by the following formula or a prodrug thereof, or a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof;
[2] The fused heterocyclic derivative or prodrug thereof, pharmacologically acceptable salt thereof, or hydrate or solvate thereof according to [1], wherein ring A is a 5-membered heteroaryl ring ;
[3] The 5-membered heteroaryl ring of ring A is represented by the formula

A fused heterocyclic derivative according to the above [2], a prodrug thereof, or a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof;

で表されるチオフェン環である、前記〔３〕記載の縮合複素環誘導体もしくはそのプロドラッグ又はその薬理学的に許容される塩、又はその水和物もしくは溶媒和物；
〔５〕 Ｒ^Ａが、ハロゲン原子、置換可低級アルキル基、ＣＯＯＷ^１又はＣＯＮＷ^２Ｗ^３（Ｗ^１〜Ｗ^３は、独立して、水素原子又は置換可低級アルキル基であるか、Ｗ^２及びＷ^３は両者が結合して隣接する窒素原子とともに置換可環状アミノ基を形成してもよい）である、前記〔１〕〜〔４〕の何れかに記載の縮合複素環誘導体もしくはそのプロドラッグ又はその薬理学的に許容される塩、又はその水和物もしくは溶媒和物；[4] The 5-membered heteroaryl ring of ring A is represented by the formula

A fused heterocyclic derivative or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, which is a thiophene ring represented by:
[5] R ^A is a halogen atom, a substitutable lower alkyl group, COOW ¹ or CONW ² W ³ (W ^{1 to} W ³ are each independently a hydrogen atom or a substitutable lower alkyl group, or W ² and W ³ may be bonded to form a substituted cyclic amino group together with the adjacent nitrogen atom), or the fused heterocyclic derivative or prodrug thereof according to any one of [1] to [4] above Or a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof;

に示す位置に結合したチオフェン環である、前記〔７〕記載の縮合複素環誘導体もしくはそのプロドラッグ又はその薬理学的に許容される塩、又はその水和物もしくは溶媒和物；
〔９〕 Ｅ^１が、酸素原子である、前記〔１〕〜〔８〕の何れかに記載の縮合複素環誘導体もしくはそのプロドラッグ又はその薬理学的に許容される塩、又はその水和物もしくは溶媒和物；
〔１０〕 Ｅ^２が、酸素原子である、前記〔１〕〜〔９〕の何れかに記載の縮合複素環誘導体もしくはそのプロドラッグ又はその薬理学的に許容される塩、又はその水和物もしくは溶媒和物；[6] The condensed heterocyclic derivative or the prodrug thereof according to [5], wherein R ^A is a lower alkyl group substituted with a group selected from a hydroxyl group, a carboxy group, and a carbamoyl group; a carboxy group; or a carbamoyl group Or a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof;
[7] The fused heterocyclic derivative or prodrug or pharmacologically acceptable salt thereof according to any one of [1] to [6], wherein m is 0 or 1, or a hydrate thereof, or Solvates;
[8] The following formula, wherein m is 1, ring A is R ^A is ring A

A fused heterocyclic derivative or a prodrug thereof, or a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof, which is a thiophene ring bonded to the position shown in
[9] The fused heterocyclic derivative or prodrug thereof or pharmaceutically acceptable salt thereof or hydrate thereof according to any one of [1] to [8], wherein E ¹ is an oxygen atom. Or a solvate;
[10] The fused heterocyclic derivative or prodrug or pharmacologically acceptable salt thereof or hydrate thereof according to any one of [1] to [9], wherein E ² is an oxygen atom. Or a solvate;

で表される環のいずれかである、前記〔１１〕記載の縮合複素環誘導体もしくはそのプロドラッグ又はその薬理学的に許容される塩、又はその水和物もしくは溶媒和物；
〔１３〕 ｎが１又は２であり、環Ｂが、Ｒ^Ｂが環Ｂの下記式

（式中、Ｒ^Ｂは前記と同じ意味をもち、Ｒ^Ｂが２つある場合、２つのＲ^Ｂは同じでも異なっていてもよい）に示す位置に結合した環のいずれかである、前記〔１２〕記載の縮合複素環誘導体もしくはそのプロドラッグ又はその薬理学的に許容される塩、又はその水和物もしくは溶媒和物；
〔１４〕 環Ｂが、式

で表される環のいずれかである、前記〔１２〕又は〔１３〕記載の縮合複素環誘導体もしくはそのプロドラッグ又はその薬理学的に許容される塩、又はその水和物もしくは溶媒和物；
〔１５〕 Ｒ^Ｂが、ハロゲン原子、置換可低級アルキル基、ＯＷ^４（Ｗ^４は、水素原子又は置換可低級アルキル基である）又はシアノ基である、前記〔１〕〜〔１４〕の何れかに記載の縮合複素環誘導体もしくはそのプロドラッグ又はその薬理学的に許容される塩、又はその水和物もしくは溶媒和物；[11] The fused heterocyclic derivative or prodrug or pharmacologically acceptable salt thereof according to any one of [1] to [10], wherein Ring B is a benzene ring, a thiophene ring or a pyridine ring. Or a hydrate or solvate thereof;
[12] Ring B is a formula

The condensed heterocyclic derivative of the above-mentioned [11], or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof;
[13] n is 1 or 2, ring B, the following formula ^{R B} is ring B

(Wherein, R ^B has the same meaning as described above, and when there are two R ^B , two R ^B may be the same or different), 12] The fused heterocyclic derivative or prodrug thereof or pharmacologically acceptable salt thereof, or hydrate or solvate thereof;
[14] Ring B is the formula

The condensed heterocyclic derivative of the above-mentioned [12] or [13], or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof;
[15] Any of [1] to [14] above, wherein R ^B is a halogen atom, a substitutable lower alkyl group, OW ⁴ (W ⁴ is a hydrogen atom or a substitutable lower alkyl group) or a cyano group. A fused heterocyclic derivative or a prodrug thereof or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof;

[16] The above [15], wherein R ^B is a halogen atom, a lower alkyl group which may be substituted with a halogen atom or OW ⁴ (W ⁴ is a hydrogen atom or a substitutable lower alkyl group). A fused heterocyclic derivative or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof;
[17] The fused heterocyclic derivative or prodrug thereof or pharmacologically acceptable salt thereof according to [16], wherein R ^B is a fluorine atom, a chlorine atom, or OW ⁴ wherein W ⁴ is a lower alkyl group. Or a hydrate or solvate thereof;
[18] The fused heterocyclic derivative or prodrug or pharmacologically acceptable salt thereof according to any one of [1] to [17], wherein U is a single bond, a methylene group or an ethylene group, or Its hydrates or solvates;
[19] X is represented by Y, -S-L-Y, -O-L-Y, -CO-L-Y, -SO 2 -L-Y, -S-Z or -O-Z A fused heterocyclic derivative or a prodrug thereof or a pharmacologically acceptable group thereof according to any one of [1] to [18] above, wherein L, Y and Z have the same meanings as described above Or a hydrate or solvate thereof;
[20] U is a single bond, wherein X is -S-L-Y, -O- L-Y, the groups represented by -CO-L-Y or _-SO 2 -L-Y (wherein, L , Y is as defined above), the fused heterocyclic derivative according to [19] above, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof;

[21] U is a methylene group, X is Y (provided that Y is —NW ⁷ W ⁸ [W ⁷ and W ⁸ are independently a hydrogen atom, a substitutable lower alkyl group or Z (provided that W ⁷ and W ⁸ may be bonded to each other to form a substituted cyclic amino group together with the adjacent nitrogen atom)), represented by —S—Z or —O—Z. A fused heterocyclic derivative or a prodrug thereof or a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof according to [19] above, wherein Z is as defined above;
[22] The fused heterocyclic derivative or the prodrug thereof according to [19] above, wherein U is an ethylene group, and X is Y (provided that Y is Z and Z is as defined above). A pharmacologically acceptable salt, or a hydrate or solvate thereof;
[23] The fused heterocyclic derivative or prodrug or pharmacologically acceptable salt thereof according to any one of [1] to [20], wherein L is a C _1-3 alkylene group, or a salt thereof Hydrates or solvates;
[24] The fused heterocyclic derivative or prodrug thereof or pharmacologically acceptable thereof according to any one of [1] to [23], wherein Z is a substituted aryl group which may be condensed. Or a hydrate or solvate thereof;
[25] The fused heterocyclic derivative according to any one of [1] to [24] or a prodrug thereof, or a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient A pharmaceutical composition;

[26] The pharmaceutical composition according to the above [25], which is a gonadotropin releasing hormone antagonist;
[27] The pharmaceutical composition according to [25] above, which is a preventive or therapeutic agent for sex hormone-dependent diseases, a reproductive regulator, a contraceptive, an ovulation inducer, or a preventive agent for sex hormone-dependent cancer postoperative recurrence
[28] Sex hormone dependent diseases are prostatic hypertrophy, uterine fibroids, endometriosis, uterine fibroma, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, polycystic ovary syndrome, erythema Selected from the group consisting of lupus, hirsutism, dwarfism, sleep disorders, acne, baldness, Alzheimer's disease, infertility, irritable bowel syndrome, prostate cancer, uterine cancer, ovarian cancer, breast cancer and pituitary tumor [27] the pharmaceutical composition according to [27] above, and [29] the pharmaceutical composition according to [25] above, which is for oral administration;
And a method of preventing or treating sex hormone-dependent diseases, a method of reproductive regulation, a method of contraception, a method of inducing ovulation, or a method of preventing recurrence after sex hormone-dependent cancer, comprising administering an effective amount thereof; Gonadotropin releasing hormone agonist, chemotherapeutic agent, peptide gonadotropin releasing hormone antagonist, 5α-reductase inhibitor, α adrenergic receptor inhibitor, aromatase inhibitor, adrenal androgen production inhibitor And a pharmaceutical composition in combination with at least one drug selected from the group of hormone therapy agents.

  Since the fused heterocyclic derivative (I) or a prodrug thereof or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof according to the present invention has an excellent GnRH antagonistic action, gonadotropin release It can be used as a prophylactic or therapeutic agent for sex hormone-dependent diseases by regulating the action of hormones and controlling production and secretion of gonadotropins and sex hormones.

The meaning of the term in this specification is as follows.
The “5-membered unsaturated hydrocarbon” means a 5-membered hydrocarbon ring having 1 or 2 double bonds.
“Heteroaryl” is a monocyclic heteroaryl having one or more heteroatoms arbitrarily selected from nitrogen, oxygen and sulfur atoms (eg, thiazole, oxazole, isothiazole, isoxazole, pyridine, pyrimidine) , Pyrazine, pyridazine, pyrrole, furan, thiophene, imidazole, pyrazole, oxadiazole, thiadiazole, triazole, tetrazole, furazane and the like.
“Substitutable” means that it may have a substituent.
“5-membered heteroaryl” means a 5-membered monocyclic heteroaryl such as thiazole, oxazole, isothiazole, isoxazole, pyrrole, furan, thiophene, imidazole, pyrazole, oxadiazole, thiadiazole, Examples include triazole and furazane rings.

“Aryl” means phenyl.
“Halogen atom” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
“Lower alkyl” is branched from 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl and the like. Means good alkyl.
“Lower alkenyl” means an optionally branched alkenyl having 2 to 6 carbon atoms such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 2-methylallyl and the like.
“Lower alkynyl” means alkynyl having 2 to 6 carbon atoms such as ethynyl and 2-propynyl.
“Lower alkylsulfonyl” means sulfonyl substituted with the above lower alkyl.
“Lower alkylsulfinyl” means sulfinyl substituted with the above lower alkyl.
“Lower alkylene” means methylene, ethylene, methylmethylene, trimethylene, dimethylmethylene, ethylmethylene, methylethylene, propylmethylene, isopropylmethylene, dimethylethylene, butylmethylene, ethylmethylmethylene, pentamethylene, diethylmethylene, dimethyltrimethylene , Alkylene having 1 to 6 carbon atoms, such as hexamethylene and diethylethylene.
“C _1-3 alkylene” means the above lower alkylene having 1 to 3 carbon atoms.
“Lower alkoxy” means carbon number such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, hexyloxy, etc. 1-6 alkoxy which may be branched is meant.
“Lower alkoxycarbonyl” means an alkoxycarbonyl having 2 to 7 carbon atoms which may be branched.
“Lower alkylthio” means alkylthio having 1 to 6 carbon atoms which may be branched.

“Cycloalkyl” means monocyclic cycloalkyl having 3 to 8 carbon atoms (for example, monocyclic cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl group, etc.).
“Heterocycloalkyl” is a 3- to 8-membered ring having 1 or 2 or more heteroatoms arbitrarily selected from a nitrogen atom, an oxygen atom and a sulfur atom, and optionally having 1 to 2 oxo groups Heterocycloalkyl (e.g., pyrrolidinyl, piperidinyl, oxopiperidinyl, morpholinyl, piperazinyl, oxopiperazinyl, thiomorpholinyl, azepanyl, diazepanyl, oxazepanyl, thiazepanyl, dioxothiazepanyl, azocanyl, tetrahydrofuranyl, tetrahydropyranyl, etc. ) And when it has a sulfur atom in the ring, the sulfur atom may be oxidized.

  “It may be condensed” means that it may be fused with one ring selected from the above cycloalkyl, the above heterocycloalkyl, the above aryl and the above heteroaryl. Examples of “fused cycloalkyl”, “fused heterocycloalkyl”, “fused aryl” and “fused heteroaryl” include, for example, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl , Benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, indazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, indolizinyl, naphthyridinyl, pteridinyl, indanyl, 1,2, 3,4-tetrahydronaphthyl, indolinyl, isoindolinyl, 2,3,4,5-tetrahydrobenzo [b] oxepinyl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl Chromanyl and the like, bond may have out either ring.

  “Cyclic amino” means a group having at least one nitrogen atom having a bonding site in the ring among the above-mentioned heterocycloalkyl which may be condensed, such as 1-pyrrolidinyl, 1-pyrrolidinyl, Piperidinyl, 1-piperazinyl, 4-morpholinyl, 4-thiomorpholinyl, 2,3,4,5,6,7-hexahydro-1H-azepin-1-yl, 1-indolinyl, 2-isoindolinyl, 3,4-dihydro- 1,5-naphthyridin-1 (2H) -yl, 1,2,3,4-tetrahydroquinolin-1-yl, 3,4-dihydroquinolin-1 (2H) -yl, 3,4-dihydroisoquinoline-2 (1H) -yl, octahydroquinolin-1 (2H) -yl, octahydroisoquinolin-2 (1H) -yl, perhydroquinolin-1-yl, 2,3-di Dro-4H-1,4-benzoxazin-4-yl, 2,3-dihydro-4H-1,4-benzothiazin-4-yl, 3,4-dihydroquinoxalin-1 (2H) -yl, 2,3 -Dihydro-4H-pyrido [3,2-b] [1,4] oxazin-4-yl, 2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl, 1,3,4 , 5-Tetrahydro-2H-2-benzazepin-2-yl, 3,4-dihydro-1,5-benzoxazepin-5 (2H) -yl, 2,3-dihydro-4,1-benzothi Azepine-1 (5H) -yl, 3,4-dihydro-1,5-benzothiazepin-5 (2H) -yl, 2,3-dihydro-4,1-benzoxazepine-1 (5H)- Yl, 2,3,4,5-tetrahydro-1H-1,5-benzo Azepin-1-yl, 2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-1-yl, 5,6,7,8-tetrahydro-4H-thieno [3,2-b] azepine- 4-yl, 3,4,5,6-tetrahydro-1-benzoazocin-1 (2H) -yl group and the like can be mentioned.

“(Di) lower alkylamino” means amino mono- or di-substituted with the above lower alkyl, and the di-substituted two lower alkyl groups may be different, and the two lower alkyl groups are both May combine to form a cyclic amino group together with the adjacent nitrogen atom.
“(Di) lower alkylcarbamoyl” means carbamoyl mono- or di-substituted with the above lower alkyl, and the two di-substituted lower alkyl groups may be different, and the two lower alkyl groups are both May combine to form a cyclic amino group together with the adjacent nitrogen atom.
“Acyl” means an optionally branched aliphatic carboxylic acid acyl having 2 to 7 carbon atoms, cycloalkyl carboxylic acid acyl, heterocycloalkyl carboxylic acid acyl, aryl carboxylic acid acyl, heteroaryl carboxylic acid acyl. .
“Acylamino” means amino substituted with acyl.

で表されるチオフェン環が特に好ましい。Ｒ^Ａとしては、ハロゲン原子、置換可低級アルキル基、ＣＯＯＷ^１、ＣＯＮＷ^２Ｗ^３（Ｗ^１〜Ｗ^３は、独立して、水素原子又は置換可低級アルキル基であるか、Ｗ^２及びＷ^３は両者が結合して隣接する窒素原子とともに置換可環状アミノ基を形成してもよい）等が好ましく、水酸基、カルボキシ基及びカルバモイル基から選択される基で置換された低級アルキル基；カルボキシ基、カルバモイル基がより好ましく、カルボキシ基が更に好ましい。ｍが２以上である場合、複数のＲ^Ａは同じでも異なっていてもよい。ｍは０又は１が好ましく、ｍが１である場合は、環上にＲ^Ａを有する環Ａが、下記式

で表されるチオフェン環が特に好ましい。この場合、Ｒ^Ａは置換可低級アルキル基、ＣＯＯＷ^１又はＣＯＮＷ^２Ｗ^３（Ｗ^１〜Ｗ^３は、独立して、水素原子又は置換可低級アルキル基であるか、Ｗ^２及びＷ^３は両者が結合して隣接する窒素原子とともに置換可環状アミノ基を形成してもよい）がより好ましい。In general formula (I), ring A is preferably a 5-membered heteroaryl, more preferably a thiophene ring,

A thiophene ring represented by the formula is particularly preferred. R ^A is a halogen atom, a substitutable lower alkyl group, COOW ¹ , CONW ² W ³ (W ^{1 to} W ³ are each independently a hydrogen atom or a substitutable lower alkyl group, or W ² and W ³ May be bonded together to form a substituted cyclic amino group together with the adjacent nitrogen atom), etc., a lower alkyl group substituted with a group selected from a hydroxyl group, a carboxy group and a carbamoyl group; a carboxy group, A carbamoyl group is more preferable, and a carboxy group is still more preferable. When m is 2 or more, the plurality of R ^A may be the same or different. m is preferably 0 or 1, and when m is 1, ring A having R ^A on the ring is represented by the following formula:

A thiophene ring represented by the formula is particularly preferred. In this case, R ^A is a substitutable lower alkyl group, COOW ¹ or CONW ² W ³ (W ^{1 to} W ³ are independently a hydrogen atom or a substitutable lower alkyl group, or W ² and W ³ are both May be combined with the adjacent nitrogen atom to form a substituted cyclic amino group).

In the general formula (I), as ^{E 1,} an oxygen atom is preferable. E ² is preferably an oxygen atom.

で表されるものが好ましく、下記式

（式中、左側の結合手は縮合ピリミジン環のＮとの結合を、右側の結合手はＵとの結合を示す）で表されるものが特に好ましい。
ｎが１又は２である場合は、環上にＲ^Ｂを有する環Ｂが、下記式

（式中、Ｒ^Ｂが結合していない結合手のうち左側の結合手は縮合ピリミジン環のＮとの結合を、右側の結合手はＵとの結合を示す）で表されるベンゼン環、チオフェン環又はピリジン環が好ましい。Ｒ^Ｂとしては、ハロゲン原子、置換可低級アルキル基、ＯＷ^４（Ｗ^４は水素原子又は置換可低級アルキル基である）、シアノ基等が好ましく、ハロゲン原子、ハロゲン原子で置換されていてもよい低級アルキル基、ＯＷ^４がより好ましく、フッ素原子、塩素原子、Ｗ^４が低級アルキル基であるＯＷ^４が特に好ましい。ｎが２である場合、複数のＲ^Ｂは同じでも異なっていてもよい。更に、環上にＲ^Ｂを有する環Ｂが、下記式

（式中、Ｒ^Ｂ１及びＲ^Ｂ２のいずれも結合していない結合手のうち左側の結合手は縮合ピリミジン環のＮとの結合を、右側の結合手はＵとの結合を示す）で表されるベンゼン環、チオフェン環又はピリジン環である場合は、Ｒ^Ｂ１としては、フッ素原子又は塩素原子が好ましく、Ｒ^Ｂ２としては、フッ素原子、メトキシ基又はエトキシ基が好ましく、メトキシ基がより好ましい。In general formula (I), as ring B, a benzene ring, a thiophene ring or a pyridine ring is preferable, and a benzene ring or a thiophene ring is more preferable. In this case, the bonding position of ring B is the following formula:

Is preferably represented by the following formula:

Particularly preferred are those represented by the formula (wherein the left bond represents a bond with N of the condensed pyrimidine ring, and the right bond represents a bond with U).
when n is 1 or 2, the ring B having R ^B on the ring, the following formula

A benzene ring represented by the formula (wherein, of the bonds in which R ^B is not bonded, the left bond represents a bond with N of the condensed pyrimidine ring, and the right bond represents a bond with U), A ring or a pyridine ring is preferred. R ^B is preferably a halogen atom, a substitutable lower alkyl group, OW ⁴ (W ⁴ is a hydrogen atom or a substitutable lower alkyl group), a cyano group, and the like, and may be substituted with a halogen atom or a halogen atom. a lower alkyl group, OW ⁴ are more preferable, and a fluorine atom, a chlorine atom, OW ^{4 W 4} is a lower alkyl group is particularly preferred. When n is 2, the plurality of R ^B may be the same or different. Further, ring ^B having RB on the ring is represented by the following formula:

(In the formula, of the bonds in which neither R ^B1 nor R ^B2 is bonded, the left bond represents the bond with N of the condensed pyrimidine ring, and the right bond represents the bond with U). In the case of a benzene ring, thiophene ring or pyridine ring, R ^B1 is preferably a fluorine atom or a chlorine atom, and R ^B2 is preferably a fluorine atom, a methoxy group or an ethoxy group, and more preferably a methoxy group.

In general formula (I), U is preferably a single bond, a methylene group or an ethylene group.
In particular, (i) when U is a single bond, X is a group represented by —S—L—Y, —O—L—Y, —CO—L—Y or —SO ₂ —L—Y ( In the formula, L is a substitutable lower alkylene group; Y is Z or —NW ⁷ W ⁸ [W ⁷ and W ⁸ are each independently a hydrogen atom, a substitutable lower alkyl group or Z (provided that W ⁷ and W ⁸ may be bonded together to form a substituted cyclic amino group together with the adjacent nitrogen atom], and Z may be condensed. A substituted cycloalkyl group, a substituted heterocycloalkyl group which may be condensed, a substituted aryl group which may be condensed or a substituted heteroaryl group which may be condensed). (Ii) When U is a methylene group, X is Y (provided that Y is -NW ⁷ W ⁸ [W ⁷ and W ⁸ are , Independently, a hydrogen atom, a substitutable lower alkyl group, or Z (but not simultaneously a hydrogen atom. W ⁷ is preferably Z), or W ⁷ and W ⁸ are adjacent to each other by bonding. A substituted cyclic amino group may be formed together with the nitrogen atom]), a group represented by -SZ or -O-Z is (iii) when U is an ethylene group, X is Y ( However, Y is Z, and Z has the same meaning as described above.
L is more preferably a C _1-3 lower alkylene group.
Z is preferably a condensed heteroaryl group which may be condensed or a substituted aryl group which may be condensed, and more preferably a substituted aryl group which may be condensed. In Z, the substituent which the substituted heteroaryl group or the substituted aryl group may have is preferably a halogen atom, a substituted lower alkyl group or a substituted lower alkoxy group, and a halogen atom; a halogen atom, a lower alkoxy A lower alkyl group which may be substituted with a group or a hydroxyl group; or a lower alkoxy group which may be substituted with a halogen atom, a lower alkoxy group or a hydroxyl group is more preferred.

Examples of the substituent that the substituted cyclic amino, substituted cycloalkyl or substituted heterocycloalkyl group may have include, for example, an oxo group, a halogen atom, a cyano group, a hydroxyl group, a substituted lower alkyl group, and a cycloalkyl group. Substituted lower alkoxy group, substituted lower alkylthio group, carboxy group, substituted lower alkoxycarbonyl group, carbamoyl group, (di) lower alkyl carbamoyl group, substituted aryl group, aryloxy group, heteroaryl group, heteroaryloxy A group, an acylamino group, and the like, and these groups may be the same or different and may be substituted plurally. However, as the NW ² W ³ is a substitutable cyclic amino group substituents which may be possessed by the formation in R ^A, except a group comprising an aryl group.
Examples of the substituent that the substituted aryl or substituted heteroaryl group may have include, for example, a halogen atom, a nitro group, a cyano group, a hydroxyl group, a substituted lower alkyl group, a cycloalkyl group, a substituted lower alkoxy group, Substituted lower alkylthio group, carboxy group, substituted lower alkoxycarbonyl group, carbamoyl group, (di) lower alkylcarbamoyl group, aryl group, aryloxy group, heteroaryl group, heteroaryloxy group, acylamino group, etc. A plurality of these groups may be the same or different and may be substituted.
Substituted cycloalkyl group which may be condensed, substituted heterocycloalkyl group which may be condensed, substituted aryl group which may be condensed and substituted heteroaryl which may be condensed In the group, the above substituents may be substituted with a plurality of the same or different condensed rings.
In the case where Z is a substituted cycloalkyl group that may be condensed or a substituted heterocycloalkyl group that may be condensed, the substituent that the group may have is a substituted aryl A group or heteroaryl group is preferred.

Substituted lower alkyl, substituted lower alkylene, substituted lower alkenyl, substituted lower alkynyl, substituted lower alkylsulfonyl, substituted lower alkylsulfinyl, substituted lower alkoxy, substituted lower alkylthio or substituted lower alkoxycarbonyl group The substituents which may be used include halogen atoms, cyano groups, hydroxyl groups, lower alkoxy groups, lower alkylthio groups, amino groups, (di) lower alkylamino groups, carboxy groups, lower alkoxycarbonyl groups, carbamoyl groups, (di ) A lower alkylcarbamoyl group, an aryl group, a heteroaryl group, etc. are mentioned, and these groups may be the same or different and may be substituted by a plurality. However, in ^RA , a group containing an aryl group and a group containing a heteroaryl group are excluded.

  An example of the method for producing the condensed heterocyclic derivative represented by the general formula (I) according to the present invention is shown below.

[Production method 1]
Among the condensed heterocyclic derivatives represented by the general formula (I) of the present invention, a compound in which E ¹ is an oxygen atom can be produced by, for example, the production method 1.

In the formula, R ¹ is a nitrile group or a lower alkoxycarbonyl group, and ring A, ring B, R ^A , R ^B , m, n, E ² , U, and X have the same meaning as described above.

Step 1-1
The amine compound ( 1 ) is reacted with a base (eg, triethylamine, N, N-diisopropylethylamine, using a reagent such as phosgene, diphosgene, triphosgene, etc. in an inert solvent (eg, tetrahydrofuran, dichloromethane, a mixed solvent thereof, etc.). In the presence of pyridine or the like, it can be converted to the isocyanate compound ( 2 ) by treatment usually at ice-cooling to reflux temperature for 30 minutes to 1 day.

Step 1-2
Isocyanate compound ( 2 ) and amine compound ( 3 ) in an inert solvent (eg, tetrahydrofuran, dichloromethane, etc.), base (eg, triethylamine, N, N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, etc.) The urea compound ( 4 ) or the condensed heterocyclic derivative (Ia) of the present invention can be produced by reacting in the presence or absence of water, usually at ice-cooling to reflux temperature for 1 hour to 3 days.

Step 1-3
The urea compound ( 4 ) is dissolved in an inert solvent (eg, tetrahydrofuran, dichloromethane, methanol, ethanol, N, N-dimethylformamide, water, etc.) with a base (eg, triethylamine, N, N-diisopropylethylamine, pyridine, 4- In the presence or absence of dimethylaminopyridine, sodium methoxide, sodium ethoxide, sodium hydride, sodium hydroxide, etc.), the reaction is usually carried out at ice-cooling to reflux temperature for 5 minutes to 3 days. The fused heterocyclic derivative (Ia) can be produced.

[Production method 2]
Among the condensed heterocyclic derivatives represented by the general formula (I) of the present invention, a compound in which E ² is an oxygen atom can be produced, for example, by the production method 2.

Ring A, ring B, R ^A , R ^B , m, n, U and X in the formula have the same meaning as described above.

Step 2-1
The amide compound ( 6 ) can be produced by condensing the carboxylic acid compound ( 5 ) and the amine compound ( 3 ) by a general acid chloride method or a condensing agent method. In the acid chloride method, for example, a carboxylic acid compound ( 5 ) is added to an additive (for example, N, N) using a reagent such as thionyl chloride or oxalyl chloride in an inert solvent (dichloromethane, 1,2-dichloroethane, toluene). In the presence or absence of N-dimethylformamide, etc., the acid chloride is usually treated by treatment at ice-cooling to reflux temperature for 30 minutes to 1 day, and then the amine compound ( 3 ) and an inert solvent ( Pyridine, dichloromethane, tetrahydrofuran, water, etc.) in the presence or absence of bases (triethylamine, N, N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, potassium carbonate, sodium bicarbonate, etc.), usually ice-cooled The reaction may be performed at a reflux temperature for 1 hour to 3 days. In the condensing agent method, for example, a carboxylic acid compound ( 5 ) and an amine compound ( 3 ) are mixed in an inert solvent (N, N-dimethylformamide, dichloromethane, tetrahydrofuran) with a condensing agent (1-ethyl-3- (3 -Dimethylaminopropyl) carbodiimide hydrochloride, dicyclohexylcarbodiimide, etc.) in the presence of additives (1-hydroxybenzotriazole, etc.), bases (triethylamine, N, N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, etc.) ) In the presence or absence, usually at room temperature to reflux temperature for 1 hour to 3 days.

Step 2-2
The amine compound ( 7 ) can be produced by reducing the nitro group of the amide compound ( 6 ) by a general catalytic reduction method or a metal hydrogen complex reduction method. In the catalytic reduction method, for example, the amide compound ( 6 ) is usually used at room temperature to reflux temperature using a catalyst (palladium carbon powder or the like) in an inert solvent (methanol, ethanol, ethyl acetate, tetrahydrofuran, acetic acid, etc.). What is necessary is just to process for 1 hour to 3 days. In the metal hydride complex reduction method, for example, an amide compound ( 6 ) is added with an additive (nickel bromide ( In the presence of II) etc., the treatment is usually carried out at ice-cold temperature to room temperature for 30 minutes to 1 day.

Step 2-3
Amine compound (7), using an inert solvent (tetrahydrofuran, dichloromethane, N, N-dimethylformamide, etc.), phosgene, diphosgene, triphosgene, a reagent such as 1,1'-carbonylbis--1H- imidazole, base By treatment in the presence or absence of (triethylamine, N, N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, sodium hydride, etc.) usually at ice-cold to reflux temperature for 30 minutes to 1 day, The fused heterocyclic derivative (Ib) of the present invention can be produced.

Step 2-4
The amine compound ( 7 ) is converted into a base (triethylamine, N, N-diisopropylethylamine, sodium hydride) using a reagent such as carbon disulfide in an inert solvent (tetrahydrofuran, N, N-dimethylformamide, methanol, ethanol). In the presence of sodium hydroxide, potassium hydroxide, etc.), the condensed heterocyclic derivative (Ic) of the present invention can be produced usually by treatment at ice-cooling to reflux temperature for 1 hour to 3 days.

Step 2-5
The amine compound ( 7 ) is converted into a base (triethylamine, N, N-diisopropylethylamine) using a reagent such as diphenylcyanocarbonimidate in an inert solvent (tetrahydrofuran, N, N-dimethylformamide, methanol, ethanol, etc.). The condensed heterocyclic derivative (Id) of the present invention is produced by treatment in the presence of sodium hydride, sodium hydroxide, potassium hydroxide, etc., usually at ice-cooling to reflux temperature for 1 hour to 3 days. Can do.

[Production method 3]
The amine compound ( 3 ) used as the raw material compound in the above production method 1 or 2 is, for example, a commercially available product, a nitro compound ( 8 ) synthesized according to a method described in the literature or a combination of general synthesis methods, etc. It can also be obtained by reduction by a conventional reduction method or the like. For example, it can be produced by the following production method 3.

Rings B, R ^B , n, U and X in the formula have the same meaning as described above.

Process 3
The amine compound ( 3 ) can be produced by reducing the nitro compound ( 8 ) by a general catalytic reduction method or a metal hydrogen complex reduction method. The catalytic reduction method uses, for example, a nitro compound ( 8 ) in an inert solvent (methanol, ethanol, ethyl acetate, tetrahydrofuran, acetic acid, etc.) and a catalyst (palladium carbon powder, rhodium carbon powder, platinum carbon powder, etc.). Usually, the treatment may be performed at room temperature to reflux temperature for 1 hour to 3 days. In the metal hydride complex reduction method, for example, a nitro compound ( 8 ) is added to an additive (nickel bromide ( 8 )) in an inert solvent (methanol, ethanol, tetrahydrofuran, etc.) using a reducing agent (sodium borohydride, etc.). In the presence of II) etc., the treatment is usually carried out at ice-cold temperature to room temperature for 30 minutes to 1 day.

  In addition, when the compound used in the above-described production method or the compound to be produced has a functional group that changes depending on the reaction conditions or inhibits the progress of the reaction, this is protected with an appropriate protecting group commonly used by those skilled in the art, Needless to say, it is removed at an appropriate stage.

  The condensed heterocyclic derivative represented by the general formula (I) according to the present invention is a prodrug having its carboxyl group, hydroxyl group and / or amino group converted by reacting a prodrug-forming reagent by a conventional method. Can do. In addition, the prodrug of the condensed heterocyclic derivative represented by the general formula (I) according to the present invention can be obtained under physiological conditions described in “Development of Drugs”, Volume 7, pages 163 to 198 (Hirokawa Shoten). It may be converted to the compound (I) of the present invention.

  The condensed heterocyclic derivative represented by the general formula (I) or a prodrug thereof can be converted into a pharmacologically acceptable salt thereof by a conventional method. Examples of such salts include inorganic acid salts such as hydrochloric acid and nitric acid; organic acid salts such as acetic acid and methanesulfonic acid; sodium salts and potassium salts; N, N′-dibenzylethylenediamine and 2-aminoethanol. And addition salts with organic bases.

  The condensed heterocyclic derivative represented by the general formula (I) or a prodrug thereof may be obtained as a hydrate or solvate in the purification or salt formation process. In the pharmaceutical composition according to the present invention, any of condensed heterocyclic derivatives or prodrugs thereof or pharmacologically acceptable salts thereof, or hydrates or solvates thereof can be used.

  Furthermore, the fused heterocyclic derivative represented by the general formula (I) or a prodrug thereof may have a tautomer, a geometric isomer and / or an optical isomer, and the pharmaceutical composition according to the present invention. Any of the isomers can be used for the mixture, and a mixture thereof can also be used.

  The condensed heterocyclic derivative (I) according to the present invention has an excellent GnRH antagonistic action, regulates the action of gonadotropin releasing hormone, and controls the production and secretion of gonadotropin and sex hormone. it can. Therefore, the fused heterocyclic derivative (I) or a prodrug thereof, or a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof according to the present invention is, for example, prostatic hypertrophy, uterine fibroid, intrauterine Membrane disease, uterine fibroma, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, polycystic ovary syndrome, lupus erythematosus, hirsutism, dwarfism, sleep disorder, acne, baldness, Alzheimer Preventive or therapeutic agent for sex hormone-dependent diseases such as illness, infertility, irritable bowel syndrome, prostate cancer, uterine cancer, ovarian cancer, breast cancer, pituitary tumor, reproductive regulator, contraceptive, ovulation inducer or sex It is extremely useful as an agent for preventing recurrence after surgery for hormone-dependent cancer.

  The pharmaceutical composition by mixing the condensed heterocyclic derivative (I) according to the present invention or a prodrug thereof or a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof and a conventional pharmaceutical carrier. Product can be prepared.

  The pharmaceutical carrier may be used in appropriate combination depending on the dosage form described later. For example, excipients such as lactose; lubricants such as magnesium stearate; disintegrants such as carboxymethylcellulose; hydroxypropylmethylcellulose and the like Binding agent; Surfactant such as macrogol; Foaming agent such as sodium bicarbonate; Solubilizing agent such as cyclodextrin; Acidity agent such as citric acid; Stabilizer such as sodium edetate; pH adjustment such as phosphate Agents and the like.

  Examples of the dosage form of the pharmaceutical composition according to the present invention include oral administration agents such as powders, granules, fine granules, dry syrups, tablets and capsules; parenteral administrations such as injections, patches and suppositories. An oral administration agent is preferable.

  The compound represented by the general formula (I) according to the present invention or a pharmacologically acceptable salt thereof or a hydrate or solvate thereof is 0.1 to 1000 mg per day for an adult, In the case of an injection, the above preparation is preferably produced so that it is administered in the range of 0.01 to 100 mg.

  The pharmaceutical composition according to the present invention may further contain other drugs. Examples of such drugs include GnRH agonists (for example, leuprorelin acetate, gonadorelin, buserelin, triptorelin, goserelin, nafarelin, histrelin, deslorelin, meterelin, resilerin, etc.), chemotherapeutic agents (for example, ifosfamide, adriamycin, pepromycin). , Cisplatin, cyclophosphamide, 5-FU, UFT, methotrexate, mitomycin C, mitoxantrone, paclitaxel, dotaxel, etc., peptidic GnRH antagonists (for example, cetrorelix, ganirex, abarelix, ozalelix, iterelix, degarelix, teverelix Etc.) 5α-reductase inhibitors (eg finasteride, dutasteride etc.), α-adrenergic receptor inhibitors (eg tamsulosin, silodosin, etc.) Rapidyl, etc.), aromatase inhibitors (eg, fadrozole, letrozole, anastrozole, formestane, etc.), adrenal androgen production inhibitors (eg, riarozole, etc.), hormone therapy agents (eg, antiestrogens (tamoxifen, Vestrants, etc.), luteinizing hormone agents (such as medroxyprogesterone), androgenic agents, estrogens, antiandrogens (such as oxendron, flutamide, nilutamide, bicalutamide, etc.)).

  The contents of the present invention will be described in more detail with reference to the following examples and test examples, but the present invention is not limited to the contents.

Reference example 1
2-Chloro-5- (3,4-dihydroquinolin-1 (2H) -ylsulfonyl) aniline

  To a suspension of 1,2,3,4-tetrahydroquinoline (3.12 g) and sodium bicarbonate (2.66 g) in tetrahydrofuran (60 mL) was added water (6 mL) and 4-chloro-3-nitrobenzenesulfonyl chloride (5. 4 g) in tetrahydrofuran (30 mL) was sequentially added and stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed successively with water, 1 mol / L hydrochloric acid, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 1-[(4-chloro-3-nitrophenyl) sulfonyl] -1,2,3,4-tetrahydroquinoline (5.0 g). This was dissolved in tetrahydrofuran (45 mL), methanol (45 mL), nickel (II) bromide (0.15 g) and sodium borohydride (1.61 g) were added under ice-cooling, and the mixture was kept at the same temperature for 30 minutes and then at room temperature. For 30 minutes. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 3/1) to obtain the title compound (4.33 g).

Reference Examples 2-11
The compounds of Reference Examples 2 to 11 listed in Tables 1 and 2 were obtained in the same manner as in Reference Example 1 using the corresponding starting materials.

Reference Example 12
2-Chloro-5- (3,4-dihydroquinolin-1 (2H) -ylmethyl) aniline To a solution of 4-chloro-3-nitrobenzyl alcohol (1 g) in methylene chloride (10 mL) was added triethylamine (1.12 mL under ice-cooling). ) And methanesulfonyl chloride (0.5 mL) were added and stirred at room temperature for 10 hours. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain mesylic acid (4-chloro-3-nitrobenzyl) (1.08 g). This was dissolved in acetonitrile (4 mL) -ethanol (4 mL), 1,2,3,4-tetrahydroquinoline (1.62 g) and a catalytic amount of sodium iodide were added, and the mixture was stirred at 60 ° C. overnight. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3/1) to give 1- (4-chloro-3-nitrobenzyl) -1,2, 3,4-tetrahydroquinoline (1.22 g) was obtained. This was dissolved in tetrahydrofuran (12 mL), methanol (12 mL), nickel (II) bromide (44 mg) and sodium borohydride (0.46 g) were added under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes and then at room temperature for 30 minutes. Stir for minutes. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 3/1) to obtain the title compound (0.79 g).

Reference Example 13
3-Benzyloxy-6-chloroaniline 4-Chloro-3-nitrophenol (0.13 g) is dissolved in N, N-dimethylformamide (3 mL), and potassium carbonate (0.31 g) and benzyl bromide (0.14 mL) are dissolved. ) And stirred at room temperature for 2 hours. The reaction mixture was diluted with diethyl ether, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was dissolved in tetrahydrofuran (3 mL), methanol (3 mL), nickel (II) bromide (8 mg) and sodium borohydride (85 mg) were added under ice-cooling, and the mixture was stirred at the same temperature for 30. For 30 minutes and then at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (0.15 g).

Reference Examples 14-17
The compounds of Reference Examples 14 to 17 described in Table 2 were obtained in the same manner as in Reference Example 13 using the corresponding starting materials.

Reference Example 18
3- (2-Phenylethyl) aniline 3-Bromonitrobenzene (1 g), Styrene (1.7 mL), Palladium (II) acetate (95 mg), Tris (2-methylphenyl) phosphine (0.3 g) and N, N -A mixture of diisopropylamine (5 mL) was heated to reflux for 24 hours. The reaction mixture was diluted with diethyl ether, washed successively with 1 mol / L hydrochloric acid, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 10/1) to give 3-((E) -2-phenylvinyl) nitrobenzene (0.76 g). ) To a solution of the obtained 3-((E) -2-phenylvinyl) nitrobenzene (0.26 g) in methanol (10 mL) was added 10% palladium carbon powder (50 mg), and the mixture was stirred at room temperature for 2 hours in a hydrogen atmosphere. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound (0.22 g).

Reference Example 19
Diethyl 2-aminothiophene-3,4-dicarboxylate To a mixture of sulfur (6.9 g), ethyl pyruvate (25 g) and ethyl cyanoacetate (24.4 g) in N, N-dimethylformamide (130 mL) at room temperature 21.8 g) was added over 30 minutes and the reaction mixture was stirred at 50 ° C. for 2 hours. Water (1 L) and saturated brine (50 mL) were added to the reaction mixture, and the mixture was extracted 3 times with diethyl ether (250 mL). The extract was dried over anhydrous magnesium sulfate and purified by silica gel column chromatography (elution solvent: diethyl ether) to obtain the title compound (28.2 g).

Reference Example 20
1- (2-Fluoro-6-methoxyphenyl) ethanol To a solution of 2-fluoro-6-methoxybenzaldehyde (0.5 g) in tetrahydrofuran (10 mL) at −78 ° C., methyllithium (1.15 mol / L diethyl ether solution, 3 4 mL) was added, and the mixture was stirred at the same temperature for 1 hour and then stirred at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.45 g).

Reference Example 21
2-Fluoro-5- [1- (2-fluoro-6-methoxyphenyl) ethoxy] aniline 4-fluoro-3-nitrophenol (synthesized by the method described in International Publication WO97 / 39064) (0.2 g), 1 A solution of-(2-fluoro-6-methoxyphenyl) ethanol (0.22 g) and triphenylphosphine (0.4 g) in tetrahydrofuran (1.5 mL) at room temperature with diisopropyl azodicarboxylate (40% toluene solution, 0.84 mL) ) And stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane to n-hexane / ethyl acetate = 8/1) to give 2-fluoro-5- [1- (2-fluoro -6-methoxyphenyl) ethoxy] -1-nitrobenzene (0.15 g) was obtained. This was dissolved in tetrahydrofuran (3 mL), methanol (3 mL), nickel (II) bromide (5 mg) and sodium borohydride (55 mg) were added under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes and then at room temperature for 30 minutes. did. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3/1) to obtain the title compound (0.11 g).

Reference Examples 22-29
The compounds of Reference Examples 22 to 29 described in Tables 3 to 4 were obtained in the same manner as in Reference Example 13 or Reference Example 21 using the corresponding starting materials.

Reference Example 30
1- [4-Fluoro-3- (tert-butoxycarbonylamino) phenyl] -2-methyl-1-propanone 1- (4-Fluorophenyl) -2-methyl-1 in concentrated sulfuric acid (10 mL) at −20 ° C. -Propanone (2.92 g) was added and stirred at the same temperature for 15 minutes. A mixture of fuming nitric acid (1.4 mL) and concentrated sulfuric acid (4.2 mL) was added at −20 ° C., and the mixture was stirred at the same temperature for 20 minutes. Ice (100 g) was added to the reaction mixture and allowed to warm to room temperature with stirring. The mixture was extracted with ethyl acetate, and the extract was washed successively with water (3 times), saturated aqueous sodium hydrogen carbonate solution (2 times) and saturated brine, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 95/5 to 85/15) to give 1- (4-fluoro-3-nitrophenyl) -2-methyl-1-propanone ( 1.8 g) was obtained. This was dissolved in ethanol (5 mL), 10% palladium carbon powder (0.36 g) was added, and the mixture was stirred at room temperature for 2 hr in a hydrogen atmosphere. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 90 / 10-83 / 17) to give 1- (3-amino-4-fluorophenyl) -2-methyl-1-propanone ( 1.45 g) was obtained. This was dissolved in tetrahydrofuran (33 mL), 4-dimethylaminopyridine (0.29 g) and di (tert-butyl) dicarbonate (3.49 g) were added, and the mixture was heated to reflux for 1.5 hours. The reaction mixture was poured into 0.5 mol / L hydrochloric acid and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane to n-hexane / ethyl acetate = 95/5) to give 1- {4-fluoro-3- [N, N-di (tert-butoxycarbonyl)]. Amino] phenyl} -2-methyl-1-propanone (1.8 g) was obtained. This was dissolved in methanol (15 mL), potassium carbonate (1.96 g) was added, and the mixture was stirred at 60 ° C. for 30 min. The reaction mixture was cooled to room temperature, water and saturated brine were added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 5/1) to obtain the title compound (1.14 g).

Reference Example 31
1- (3-Amino-4-fluorophenyl) -2- (5-fluoro-2-methoxyphenyl) -2-methyl-1-propanone 1- [4-Fluoro-3- (tert-butoxycarbonylamino) phenyl ] -2-Methyl-1-propanone (0.11 g), 2-bromo-4-fluoroanisole (0.057 mL), palladium (II) acetate (4.5 mg), tri (tert-butyl) tetrafluoroborate A mixture of phosphine (5.8 mg) and sodium tert-butoxide (96 mg) in tetrahydrofuran (1 mL) was stirred at 70 ° C. for 3 days under an argon atmosphere. After adding water to the reaction mixture and stirring for 10 minutes, the mixture was poured into 1 mol / L hydrochloric acid and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 10/1) to give 1- [4-fluoro-3- (tert-butoxycarbonylamino) phenyl] -2- (5-fluoro -2-Methoxyphenyl) -2-methyl-1-propanone (45 mg) was obtained. This was dissolved in hydrochloric acid (4 mol / L ethyl acetate solution, 3 mL) and stirred overnight at room temperature. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4 / 1-3 / 1) to give the title compound (25 mg).

Reference Examples 32-35
The compounds of Reference Examples 32 to 35 listed in Tables 4 to 5 were obtained in the same manner as in Reference Example 31 using the corresponding starting materials.

Reference Example 36
3- (1-phenylethylthio) aniline To a mixture of 3-mercaptoaniline (1 g) and potassium carbonate (1.21 g) in N, N-dimethylformamide (20 mL) was added 1-phenylethyl bromide (1.2 mL), Stir at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane to n-hexane / ethyl acetate = 1/1) to obtain the title compound (1.78 g).

Reference Example 37
The compound of Reference Example 37 described in Table 5 was obtained in the same manner as in Reference Example 36 using the corresponding starting materials.

Reference Example 38
3- (1-Methyl-1-phenylethylthio) aniline To a mixed solution of water (1.6 mL) -concentrated sulfuric acid (1.6 mL) was added 3-nitrothiophenol (0.5 g), and the mixture was stirred at room temperature for 1 hour. . A solution of α-methylstyrene (0.38 g) in tetrahydrofuran (1.6 mL) was added to the mixture, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane to n-hexane / ethyl acetate = 3/2) to give 3- (1-methyl-1-phenylethylthio) nitrobenzene (0.88 g). It was. This was dissolved in tetrahydrofuran (10 mL), methanol (10 mL), nickel (II) bromide (35 mg) and sodium borohydride (0.37 g) were added under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes and then at room temperature for 1 hour. Stir. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane to n-hexane / ethyl acetate = 3/2) to obtain the title compound (0.69 g).

Reference Example 39
3-Amino-4-fluoro-N-methyl-N-phenylbenzamide To a solution of 4-fluoro-3-nitrobenzoic acid (2 g) in methylene chloride (50 mL) was added N, N-dimethylformamide (0.01 mL) and oxalyl chloride. (6.86 g) was added and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. A solution of the residue in tetrahydrofuran (10 mL) was added to a mixture of N-methylaniline (1.22 g) and sodium bicarbonate (2.72 g) in tetrahydrofuran (20 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed successively with 1 mol / L hydrochloric acid, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 4-fluoro-3-nitro-N-methyl-N-phenylbenzamide ( 2.95 g) was obtained. This was dissolved in tetrahydrofuran (50 mL), methanol (50 mL), nickel (II) bromide (0.12 g) and sodium borohydride (1.26 g) were added under ice-cooling, and the same temperature was maintained for 30 minutes and then at room temperature. Stir for 30 minutes. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1/1) to obtain the title compound (2.33 g).

Reference Example 40
The compound of Reference Example 40 described in Table 5 was obtained in the same manner as in Reference Example 39 using the corresponding starting materials.

Reference Examples 41-42
The compounds of Reference Examples 41 to 42 listed in Table 5 were obtained in the same manner as in Reference Example 21 using the corresponding starting materials.

Reference Example 43
4-Fluoro-2-methoxy-5-nitrobenzenesulfonyl chloride N, N-dimethylformamide of 3-fluoro-4-nitrophenol (2.56 g), potassium carbonate (4.5 g) and methyl iodide (4.63 g) (15 mL) The mixture was stirred overnight at room temperature. The reaction mixture was poured into water and washed with diethyl ether. The extract was washed twice with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 3-fluoro-4-nitroanisole (2.56 g). This was dissolved in 1,2-dichloroethane (13 mL), chlorosulfonic acid (1.3 mL) was added under ice cooling, and the mixture was heated to reflux for 4 hours. The reaction mixture was diluted with methylene chloride, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 2/1) to obtain the title compound (0.51 g).

Reference Examples 44-69
The compounds of Reference Examples 44 to 69 described in Tables 6 to 9 were obtained in the same manner as in Reference Example 1 using the corresponding starting materials.

Reference Example 70
4-Amino-5-methylthiophene-2,3-dicarboxylic acid dimethyl hydrochloride To methanol (15 mL) was added sodium (0.38 g) under ice-cooling, and the mixture was stirred at the same temperature until the sodium dissolved. Ethyl 2-mercaptopropionate (1.81 g) and dimethyl fumarate (2.17 g) were added to the reaction mixture, and the mixture was heated to reflux for 3 hours. The reaction mixture was cooled to room temperature, water (100 mL) was added, and the mixture was washed with diethyl ether. The aqueous layer was ice-cooled, acidified with 2 mol / L hydrochloric acid, and extracted twice with ethyl acetate. The extracts were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4 / 1-3 / 1) to give 5-methyl-4-oxo-2,3-bismethoxycarbonyltetrahydrothiophene (2.68 g). ) This was dissolved in methanol (8 mL), hydroxylammonium chloride (0.92 g) was added, and the mixture was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature, ethyl acetate (24 mL) was added, and the mixture was stirred for 10 min. The precipitate was collected by filtration, washed with ethyl acetate, and dried under reduced pressure to give the title compound (0.77 g).

Reference Examples 71-72
The compounds of Reference Examples 71 to 72 shown in Table 9 were obtained in the same manner as in Reference Example 30 using the corresponding starting materials.

Reference Examples 73-77
The compounds of Reference Examples 73 to 77 shown in Tables 9 to 10 were obtained in the same manner as in Reference Example 31 using the corresponding starting materials.

Reference Example 78
4-Bromo-2- (tert-butoxycarbonylamino) -1-fluorobenzene 1-bromo-4-fluoro-3-nitrobenzene (1.56 g), nickel (II) bromide (78 mg), methanol (28 mL) and Sodium borohydride (805 mg) was added to a mixture of tetrahydrofuran (28 mL) under ice-cooling, and the mixture was stirred at the same temperature for 30 min and at room temperature for 30 min. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. did. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 5-bromo-2-fluoroaniline (1.3 g). This was dissolved in tetrahydrofuran (30 mL), 4-dimethylaminopyridine (0.26 g) and di (tert-butyl) dicarbonate (3.1 g) were added, and the mixture was heated to reflux for 1.5 hours. The reaction mixture was poured into 0.5 mol / L hydrochloric acid and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Methanol (21 mL) and potassium carbonate (2.94 g) were added to the residue, and the mixture was heated to reflux for 2 hours. Water was added to the reaction mixture, and the mixture was poured into saturated brine and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 95/5) to obtain the title compound (1.72 g).

Reference Example 79
2- (3-Amino-4-fluorophenyl) -1- (2-methoxyphenyl) -2-methyl-1-propanone 1- (2-methoxyphenyl) -2-methyl-1-propanone (0.58 g) 4-bromo-2- (tert-butoxycarbonylamino) -1-fluorobenzene (0.94 g), palladium (II) acetate (37 mg), tri (tert-butyl) phosphine tetrafluoroborate (47 mg) and sodium A mixture of tert-butoxide (0.78 g) in tetrahydrofuran (10 mL) was stirred at 60 ° C. overnight under an argon atmosphere. After adding water to the reaction mixture and stirring for 10 minutes, the mixture was poured into 1 mol / L hydrochloric acid and extracted with diethyl ether. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 95/5 to 85/15) to give 2- [3- (tert-butoxycarbonylamino) -4-fluorophenyl] -1- (2-Methoxyphenyl) -2-methyl-1-propanone (0.91 g) was obtained. The resulting 2- [3- (tert-butoxycarbonylamino) -4-fluorophenyl] -1- (2-methoxyphenyl) -2-methyl-1-propanone (0.34 g) was added to hydrochloric acid (4 mol / L acetic acid). Ethyl solution, 3 mL) was added and stirred at room temperature for 3 hours. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (0.22 g).

Reference examples 80-81
The compounds of Reference Examples 80 to 81 listed in Table 10 were obtained in the same manner as in Reference Example 79 using the corresponding starting materials.

Reference Example 82
The same as in Reference Example 21, except that phenol was used instead of 4-fluoro-3-nitrophenol and 4-chloro-3-nitrobenzyl alcohol was used instead of 1- (2-fluoro-6-methoxyphenyl) ethanol. The compound of Reference Example 82 described in Table 11 was obtained by the method.

Reference Example 83
2-Chloro-5- (2-phenylethyl) aniline To a suspension of 4-chloro-3-nitrobenzaldehyde (1 g) and benzyltriphenylphosphonium bromide (2.34 g) in toluene (35 mL) was added sodium hydride (55% , 0.28 g) and stirred at room temperature overnight. 1 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with methylene chloride. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 10/1) to give 2-chloro-5-((Z) -2-phenylvinyl) -1-nitrobenzene (0.79 g). Got. The obtained 2-chloro-5-((Z) -2-phenylvinyl) -1-nitrobenzene (0.16 g) was dissolved in ethanol (6 mL) -methanol (2 mL), and 5% rhodium carbon powder (20 mg). And morpholine (5 mg) were added, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 5/1) to give the title compound (87 mg).

Reference Example 84
1- (tert-butoxycarbonylamino) -5-ethynyl-2-fluorobenzene 4-bromo-2- (tert-butoxycarbonylamino) -1-fluorobenzene (0.57 g), trimethylsilylacetylene (0.55 mL), A mixture of tetrakis (triphenylphosphine) palladium (0) (23 mg) and cuprous iodide (7 mg) in N, N-diisopropylamine (5.7 mL) was stirred at 80 ° C. overnight. The reaction mixture was cooled to room temperature and diluted with diethyl ether. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 15/1) to give 1- (tert-butoxycarbonylamino) -2-fluoro-5-trimethylsilylethynylbenzene (0.6 g). Got. This was dissolved in tetrahydrofuran (10 mL), tetra (n-butyl) ammonium fluoride (1 mol / L tetrahydrofuran solution, 2.4 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 20/1 to 10/1) to obtain the title compound (0.34 g).

Reference Example 85
2-Bromo-3,4-difluoroanisole To a solution of 3,4-difluoroanisole (2 mL) in tetrahydrofuran (50 mL) at −78 ° C. was added n-butyllithium (2.67 mol / L n-hexane solution, 6.95 mL). In addition, the mixture was stirred at the same temperature for 30 minutes. Bromine (1.04 mL) was added to the reaction mixture, and the mixture was stirred at −78 ° C. for 15 minutes and under ice cooling for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane to n-hexane / ethyl acetate = 9/1) to obtain the title compound (0.91 g).

Reference Example 86
2-Fluoro-5- (2-phenylethyl) aniline 1- (tert-butoxycarbonylamino) -5-ethynyl-2-fluorobenzene (0.11 g), iodobenzene (0.1 g), tetrakis (triphenylphosphine) ) A mixture of palladium (0) (16 mg) and cuprous iodide (5 mg) in N, N-diisopropylamine (2 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 10/1) to give 1- (tert-butoxycarbonylamino) -2-fluoro-5-phenylethynylbenzene (0.14 g). Obtained. This was dissolved in ethyl acetate (3 mL), 10% palladium carbon powder (50 mg) was added, and the mixture was stirred at room temperature for 2 hr in a hydrogen atmosphere. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain 1- (tert-butoxycarbonylamino) -2-fluoro-5- (2-phenylethyl) benzene (0.11 g). Hydrochloric acid (4 mol / L ethyl acetate solution, 3 mL) was added thereto, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 8/1 to 5/1) to obtain the title compound (53 mg).

Reference Examples 87-99
The compounds of Reference Examples 87 to 99 described in Tables 11 to 13 were obtained in the same manner as in Reference Example 86 using the corresponding starting materials.

Reference Example 100
2-Fluoro-4-methoxy-5- (2-phenylethyl) aniline 2-bromo-5-fluoro-4-nitroanisole (0.46 g), phenylacetylene (67 mg), tetrakis (triphenylphosphine) palladium (0 ) (38 mg), and cuprous iodide (13 mg) in N, N-diisopropylamine (5 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 10/1 to 5/1) to give 5-fluoro-4-nitro-2-phenylethynylanisole (0.18 g). It was. This was dissolved in ethyl acetate (5 mL), 10% palladium carbon powder (0.45 g) was added, and the mixture was stirred at room temperature for 3 hours in a hydrogen atmosphere. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 10/1 to 4/1) to obtain the title compound (87 mg).

Reference Example 101
2-Fluoro-5- [2- (2-methoxyphenyl) -1,1-dimethylethyl] aniline 2- [3- (tert-butoxycarbonylamino) -4-fluorophenyl] -1- (2-methoxyphenyl) ) -2-Methyl-1-propanone (0.59 g) in a tetrahydrofuran (7.5 mL) -water (0.75 mL) mixture was added sodium borohydride (0.17 g), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4/1) to give 2- [3- (tert-butoxycarbonylamino) -4-fluorophenyl] -1- (2- Methoxyphenyl) -2-methyl-1-propanol (0.54 g) was obtained. This was dissolved in ethanol (8 mL) -tetrahydrofuran (3 mL), 2 mol / L hydrochloric acid (0.2 mL) and 10% palladium carbon powder (0.27 g) were added, and the mixture was stirred at room temperature for 5 hours in a hydrogen atmosphere. Sodium hydrogen carbonate was added to the reaction mixture, and the mixture was stirred for 10 minutes. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 7/1) to give 2- [3- (tert-butoxycarbonylamino) -4-fluorophenyl] -1- (2- Methoxyphenyl) -2-methylpropane (0.15 g) was obtained. Hydrochloric acid (4 mol / L ethyl acetate solution, 3 mL) was added thereto, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (0.11 g).

Reference Example 102
4-Chloro-3-nitrothiophenol 4-Chloro-3-nitroaniline (5.18 g) was added to concentrated hydrochloric acid (30 mL) under ice cooling, and the mixture was stirred at the same temperature for 5 min. A solution of sodium nitrite (3.1 g) in water (30 mL) was added to the mixture under ice cooling, the temperature was raised to 50 ° C., and a solution of potassium dithiocarbonate O-ethyl (14.4 g) in water (60 mL) was added. Stir at 50 ° C. for 1 hour. The reaction mixture was cooled to room temperature and extracted twice with diethyl ether. The extracts were combined, washed successively with 1 mol / L aqueous sodium hydroxide solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane to n-hexane / ethyl acetate = 7/3) to give O-ethyl S- (4-chloro-3-nitrophenyl) dithiocarbonate (2. 96 g) was obtained. This was dissolved in tetrahydrofuran (50 mL), added to a suspension of lithium aluminum hydride (1.62 g) in tetrahydrofuran (50 mL) under ice cooling, and stirred at room temperature for 10 minutes. The reaction mixture was ice-cooled, water (1.8 mL), 15% aqueous sodium hydroxide solution (1.8 mL) and water (5.4 mL) were added, and the mixture was stirred at room temperature for 30 min. The insoluble material was removed by filtration, the filtrate was diluted with ethyl acetate, washed successively with 1 mol / L hydrochloric acid, water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 9/1 to 1/9) to obtain the title compound (1.28 g).

Reference Example 103
5-Benzylthio-2-chloroaniline Potassium carbonate (0.44 g) was added to a solution of 4-chloro-3-nitrothiophenol (0.4 g) and benzyl bromide (0.3 mL) in N, N-dimethylformamide (6 mL). In addition, the mixture was stirred at room temperature for 15 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane to n-hexane / ethyl acetate = 9/1) to give 1-benzylthio-4-chloro-3-nitrobenzene (0.54 g). This was dissolved in methanol (5 mL) -tetrahydrofuran (5 mL), nickel (II) bromide (21 mg) and sodium borohydride (0.22 g) were added under ice cooling, and the mixture was stirred at the same temperature for 30 minutes and at room temperature for 1 minute. Stir for hours. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane to n-hexane / ethyl acetate = 1/1) to obtain the title compound (0.38 g).

Reference Example 104
2-Fluoro-5-mercaptoaniline 5-Bromo-2-fluoroaniline (4.15 g), methyl 3-mercaptopropionate (2.62 g), 4,5-bis (diphenylphosphino) -9,9-dimethyl To a mixture of xanthene (0.63 g) and N, N-diisopropylethylamine (5.64 g) in 1,4-dioxane (80 mL) was added tris (dibenzylideneacetone) dipalladium (0) (0.3 g) and an argon atmosphere. The mixture was heated under reflux overnight. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 20/1 to 5/1 to 2/1) to give 2-fluoro-5- (2-methoxycarbonylethylthio) aniline ( 4.62 g) was obtained. This was dissolved in tetrahydrofuran (120 mL), potassium tert-butoxide (1 mol / L tetrahydrofuran solution, 80.6 mL) was added at −78 ° C., and the mixture was stirred at the same temperature for 15 min. 1 mol / L hydrochloric acid (81 mL) was added to the reaction mixture, and the mixture was warmed to room temperature and stirred for 5 minutes. The mixture was poured into ethyl acetate and the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4/1) to give the title compound (1.85 g).

Reference Example 105
2-Fluoro-6-methoxybenzyl alcohol To a solution of 2-fluoro-6-methoxybenzaldehyde (0.63 g) in tetrahydrofuran (5 mL) was added water (0.5 mL) and sodium borohydride (0.17 g), and at room temperature. Stir for 1 hour. The reaction mixture was diluted with water and extracted with diethyl ether. The extract was washed with saturated brine, and the solvent was evaporated under reduced pressure to give the title compound (0.58 g).

Reference Examples 106-107
The compounds of Reference Examples 106 to 107 listed in Table 14 were obtained in the same manner as in Reference Example 105 using the corresponding starting materials.

Reference Example 108
2-Fluoro-6-methoxybenzyl bromide To a solution of 2-fluoro-6-methoxybenzyl alcohol (0.78 g) and triethylamine (0.91 mL) in ethyl acetate (12 mL) under ice-cooling, methanesulfonyl chloride (0.43 mL). And stirred at the same temperature for 30 minutes. The insoluble material was removed by filtration, and the insoluble material was washed with ethyl acetate (4 mL). The filtrate and washings were combined, lithium bromide monohydrate (2.62 g) was added, and the mixture was stirred at 55 ° C. for 2 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane to n-hexane / ethyl acetate = 7/3) to obtain the title compound (0.82 g).

Reference Examples 109-110
The compounds of Reference Examples 109 to 110 listed in Table 14 were obtained in the same manner as in Reference Example 108 using the corresponding starting materials.

Reference Example 111
2- (5-Fluoro-2-methoxyphenyl) -2-propanol To a solution of 5-fluoro-2-methoxybenzaldehyde (1 g) in acetone (4 mL) was added potassium permanganate (1.54 g) in water (16 mL) at room temperature. The solution was added and heated to reflux for 4 hours. The reaction mixture was cooled to room temperature, 2 mol / L aqueous sodium hydroxide solution (5.2 mL) was added, and the insoluble material was removed by filtration. The filtrate was washed with ethyl acetate, acidified by adding 2 mol / L hydrochloric acid to the aqueous layer, and extracted twice with ethyl acetate. The extracts were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1/1 to ethyl acetate) to give 5-fluoro-2-methoxybenzoic acid (0.66 g). This was dissolved in N, N-dimethylformamide (15 mL), potassium carbonate (0.63 g) and methyl iodide (0.26 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give methyl 5-fluoro-2-methoxybenzoate (0.7 g). Obtained. This was dissolved in tetrahydrofuran (10 mL), methylmagnesium iodide (3.0 mol / L diethyl ether solution, 3.82 mL) was added under ice cooling, and the mixture was stirred at room temperature for 2 hr. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane to n-hexane / ethyl acetate = 1/1) to obtain the title compound (0.65 g).

Reference Examples 112-113
The compounds of Reference Examples 112 to 113 listed in Table 14 were obtained in the same manner as in Reference Example 111 using the corresponding starting materials.

Reference Example 114
2-Fluoro-5- (2-fluorobenzylthio) aniline To a solution of 2-fluoro-5-mercaptoaniline (0.13 g) and 2-fluorobenzyl bromide (0.12 mL) in N, N-dimethylformamide (5 mL) Potassium carbonate (0.25 g) was added and stirred at room temperature for 30 minutes. The reaction mixture was diluted with diethyl ether, washed successively with water (twice) and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 6/1) to give the title compound (0.17 g).

Reference Examples 115-126
The compounds of Reference Examples 115 to 126 shown in Tables 15 to 16 were obtained in the same manner as in Reference Example 114 using the corresponding starting materials.

Reference Example 127
2-Fluoro-5- (1-methyl-1-phenylethylthio) aniline To a mixture of water (10 mL) and concentrated sulfuric acid (10 mL) at room temperature, 2-fluoro-5-mercaptoaniline (1.85 g) and 2- A solution of phenyl-2-propanol (1.76 g) in tetrahydrofuran (10 mL) was sequentially added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 6 / 1-3 / 1) to give the title compound (1.55 g).

Reference examples 128-141
The compounds of Reference Examples 128 to 141 listed in Tables 16 to 18 were obtained in the same manner as in Reference Example 127 using the corresponding starting materials.

Reference Example 142
4-Fluoro-2-methoxy-5-nitrophenol Ethyl chloroformate (1) was added to a solution of 4-fluoro-2-methoxyphenol (1.42 g) and triethylamine (1.67 mL) in methylene chloride (20 mL) under ice-cooling. .05 mL) was added and stirred at room temperature for 3 days. The reaction mixture was poured into 0.5 mol / L hydrochloric acid and extracted with diethyl ether. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Concentrated sulfuric acid (7 mL) was added to the residue under ice cooling, and the mixture was stirred at the same temperature for 15 minutes. Under ice-cooling, a mixture of fuming nitric acid (0.7 mL) and concentrated sulfuric acid (1 mL) was added dropwise, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was poured into ice and stirred at room temperature for 30 minutes. The mixture was extracted with ethyl acetate, and the extract was washed successively with water (twice) and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 90 / 10-67 / 33) to give 2-ethoxycarbonyloxy-5-fluoro-4-nitroanisole (0.48 g). Obtained. Methanol (8 mL) and sodium hydrogen carbonate (0.31 g) were added thereto, and the mixture was stirred at room temperature for 42 hours. The reaction mixture was poured into 0.5 mol / L hydrochloric acid and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was suspended in a mixed solvent (n-hexane / ethyl acetate = 4/1), collected by filtration, and dried under reduced pressure to obtain the title compound (0.25 g).

Reference Examples 143 to 147
The compounds of Reference Examples 143 to 147 described in Tables 18 to 19 were obtained in the same manner as in Reference Example 142 using the corresponding starting materials.

Reference Example 148
2-Ethoxy-4-fluoro-5-nitrophenol 4′-fluoro-2′-hydroxyacetophenone (3.08 g), cesium carbonate (13.0 g) and sodium iodide (0.6 g) in N, N-dimethyl Bromoethane (2.24 mL) was added to a suspension of formamide (20 mL) and stirred overnight at room temperature. The reaction mixture was poured into water and extracted with diethyl ether. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. 3-Chloroperbenzoic acid (4.97 g) was added to a solution of the residue and 4,4′-thiobis (6-tert-butyl-o-cresol) (39 mg) in methylene chloride (57.6 mL) under ice cooling, Heated to reflux overnight. The reaction mixture was ice-cooled, 10% aqueous sodium sulfite solution was added, and the mixture was stirred for 20 min. The organic layer was separated, washed successively with water (3 times), saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in methanol (10 mL) -tetrahydrofuran (20 mL), sodium methoxide (28% methanol solution, 5 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into 0.5 mol / L hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 2-ethoxy-4-fluorophenol (3.0 g). The title compound was obtained in the same manner as in Reference Example 142 using this instead of 4-fluoro-2-methoxyphenol.

Reference Example 149
The compound of Reference Example 149 described in Table 19 was obtained in the same manner as in Reference Example 20 using the corresponding starting materials.

Reference Example 150
2- [2- (tert-Butyldimethylsilyloxy) ethoxy] benzyl alcohol To a suspension of 2-hydroxybenzyl alcohol (0.4 g) and potassium carbonate (0.67 g) in N, N-dimethylformamide (6 mL), 2- (tert-Butyldimethylsilyloxy) ethyl bromide (1.05 mL) was added and stirred at room temperature overnight. The reaction mixture was diluted with diethyl ether, washed successively with water, 1 mol / L aqueous sodium hydroxide solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 5/1) to obtain the title compound (0.32 g).

Reference Example 151
The compound of Reference Example 151 shown in Table 19 was obtained in the same manner as in Reference Example 150 using the corresponding starting materials.

Reference Example 152
2- (tert-butyldimethylsilyloxymethyl) benzyl alcohol 1,2-benzenedimethanol (2 g) and imidazole (1.13 g) in N, N-dimethylformamide (30 mL) were added to tert-butyldimethylchlorosilane (2 0.08 g) was added and stirred at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate, washed successively with 1 mol / L hydrochloric acid, water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane to n-hexane / ethyl acetate = 3/2) to obtain the title compound (1.46 g).

Reference Examples 153 to 154
The compounds of Reference Examples 153 to 154 shown in Table 20 were obtained in the same manner as in Reference Example 152 using the corresponding starting materials.

Reference Example 155
2,3-difluoro-6- (2-methoxyethoxy) benzyl alcohol 2,3-difluoro-6-hydroxybenzaldehyde (0.63 g) and potassium carbonate (0.83 g) in N, N-dimethylformamide (4 mL) 2-Methoxyethyl bromide (0.45 mL) was added to the turbid solution and stirred at room temperature for 3 days. The reaction mixture was poured into water and extracted with diethyl ether. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 85 / 15-60 / 40) to give 2,3-difluoro-6- (2-methoxyethoxy) benzaldehyde (0.62 g) Got. This was dissolved in tetrahydrofuran (6 mL), water (0.6 mL) and sodium borohydride (0.12 g) were added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.61 g).

Reference Examples 156 to 159
The compounds of Reference Examples 156 to 159 described in Table 20 were obtained in the same manner as in Reference Example 155 using the corresponding starting materials.

Reference Example 160
1- (2,3-Difluoro-6-methoxyphenyl) -1-cyclobutanol To a solution of 3,4-difluoroanisole (2.47 g) in tetrahydrofuran (50 mL) at −78 ° C. was added n-butyllithium (2.64 mol / L n-hexane solution, 6.5 mL) was added, and the mixture was stirred at the same temperature for 30 minutes. A solution of cyclobutanone (1 g) in tetrahydrofuran (20 mL) was added to the reaction mixture, and the mixture was stirred at the same temperature for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 5/1) to obtain the title compound (2.69 g).

Reference Example 161
2-chloro-5- (1-methyl-1-phenylethoxy) aniline 4-chloro-3-nitrophenol (0.5 g), tri (n-butyl) phosphine (0.72 mL) and 2-phenyl-2- To a solution of propanol (0.26 g) in tetrahydrofuran (5 mL) was added 1,1′-azobis (N, N-dimethylformamide) (0.5 g), and the mixture was stirred at 60 ° C. for 20 hours. The reaction mixture was diluted with diethyl ether, and the insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane to n-hexane / ethyl acetate = 10/1) to give 2-chloro-5- (1-methyl-1- Phenylethoxy) -1-nitrobenzene (0.19 g) was obtained. This was dissolved in tetrahydrofuran (3.5 mL), methanol (3.5 mL), nickel (II) bromide (11 mg) and sodium borohydride (0.12 g) were added under ice-cooling, and then at the same temperature for 30 minutes. Stir at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3/1) to obtain the title compound (0.14 g).

Reference Examples 162-166
The compounds of Reference Examples 162 to 166 listed in Table 21 were obtained in the same manner as in Reference Example 161 using the corresponding starting materials.

Reference examples 167 to 308
The compounds of Reference Examples 167 to 308 described in Tables 22 to 41 were obtained in the same manner as in Reference Example 13 or Reference Example 21 using the corresponding starting materials.

Reference Example 309
4-cyano-2-fluoro-5- (2,3-difluoro-6-methoxybenzyloxy) aniline instead of 5-bromo-2-fluoroaniline 4-bromo-2-fluoro-5- (2,3- 4-bromo-2-fluoro-5- (2,3-difluoro-6-methoxybenzyloxy) -1- (tert-butoxy) in the same manner as in Reference Example 78 using difluoro-6-methoxybenzyloxy) aniline. Carbonylamino) benzene was synthesized. A mixture of this compound (0.24 g) and copper (I) cyanide (90 mg) in N-methyl-2-pyrrolidone (1 mL) was stirred at an external temperature of 220 ° C. for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 2/1 to 1/1) to give the title compound (54 mg).

Reference Example 310
4-fluoro-3- (2,3-difluoro-6-methoxybenzyloxy) aniline 4-fluoro-3-hydroxybenzoic acid (0.19 g), 2,3-difluoro-6-methoxybenzyl bromide (0.6 g ) And potassium carbonate (0.5 g) in N, N-dimethylformamide (3 mL) was stirred at room temperature for 8 hours. The reaction mixture was poured into water and extracted with diethyl ether. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (6 mL), methanol (3 mL), water (3 mL) and lithium hydroxide monohydrate (0.5 g) were added, and the mixture was stirred at room temperature for 1 hr. 1 mol / L hydrochloric acid (15 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was suspended in a mixed solvent (n-hexane / ethyl acetate = 4/1), collected by filtration, and dried under reduced pressure to give 4-fluoro-3- (2,3-difluoro-6-methoxybenzyloxy) benzoic acid. (0.31 g) was obtained. This was dissolved in 1,4-dioxane (4 mL), triethylamine (0.41 mL) and diphenylphosphoryl azide (0.21 mL) were added, and the mixture was stirred at room temperature for 1 hour and then heated to reflux for 4 hours. A 1 mol / L aqueous sodium hydroxide solution (4 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 2/1 to 1/1), methylene chloride was added to the crude product, insoluble matter was filtered off, and the solvent of the filtrate was reduced under reduced pressure. The bottom compound was distilled off to obtain the title compound (70 mg).

Reference Examples 311 to 321
The compounds of Reference Examples 311 to 321 listed in Tables 41 to 43 were obtained in the same manner as in Reference Example 13 or Reference Example 21 using the corresponding starting materials.

Reference Example 322
The compound of Reference Example 322 described in Table 43 was obtained in the same manner as in Reference Example 160 using the corresponding starting materials.

Reference examples 323 to 324
The compounds of Reference Examples 323 to 324 described in Table 43 were obtained in the same manner as in Reference Example 161 using the corresponding starting materials.

Reference Example 325
2,3-Difluoro-6-methoxyphenol To a solution of 2,3-difluoro-6-methoxybenzaldehyde (2.58 g) in methylene chloride (45 mL) was added 3-chloroperbenzoic acid (5.97 g) under ice cooling. , Heated to reflux overnight. The reaction mixture was ice-cooled, 10% aqueous sodium sulfite solution was added, and the mixture was stirred for 20 min. The organic layer was separated, washed successively with water (twice), saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (15 mL) -methanol (7.5 mL), sodium methoxide (28% methanol solution, 3.75 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into 1 mol / L hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent: n-hexane to n-hexane / ethyl acetate = 2/3) and aminopropyl silica gel column chromatography (elution solvent: ethyl acetate / methanol = 9/1 to 3/2). Purification was performed sequentially to obtain the title compound (1.7 g).

Reference Example 326
The compound of Reference Example 326 described in Table 43 was obtained in the same manner as in Reference Example 325 using the corresponding starting materials.

Reference Example 327
2,4-Difluoro-5-nitrobenzyl alcohol Concentrated sulfuric acid (6 mL) was added to a methylene chloride (6 mL) solution of 2,4-difluorobenzaldehyde (2.27 g) under ice cooling, and the mixture was stirred for 15 minutes. Fuming nitric acid (1 mL) was added to the mixture under ice cooling, and the mixture was stirred at the same temperature for 30 minutes and then at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, water was added and the organic layer was separated. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution (twice), water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane to n-hexane / ethyl acetate = 7/3) to obtain 2,4-difluoro-5-nitrobenzaldehyde (2.63 g). The obtained 2,4-difluoro-5-nitrobenzaldehyde (1 g) was dissolved in tetrahydrofuran (15 mL), sodium borohydride (0.3 g) was added under ice cooling, and the mixture was stirred at room temperature for 5 minutes. 1 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane to n-hexane / ethyl acetate = 1/1) to obtain the title compound (0.76 g).

Reference Example 328
The compound of Reference Example 328 shown in Table 43 was obtained in the same manner as in Reference Example 327 using the corresponding starting materials.

Reference examples 329 to 331
Instead of 4-fluoro-3-nitrophenol, 2,3-difluoro-6-methoxyphenol or 2,3-difluoro-6- (2-methoxyethoxy) phenol is used, and 1- (2-fluoro-6-methoxy is used. Similar to Reference Example 21, using 4-fluoro-3-nitrobenzyl alcohol or 2,4-difluoro-5-nitrobenzyl alcohol or 4-fluoro-2-methoxy-5-nitrobenzyl alcohol instead of (phenyl) ethanol The compounds of Reference Examples 329 to 331 described in Table 44 were obtained by the method described above.

Reference Example 332
2,3-difluoro-6- (2-methoxyethoxy) aniline To a suspension of 3,4-difluorophenol (1.43 g) and cesium carbonate (4.89 g) in N, N-dimethylformamide (10 mL) Methoxyethyl bromide (0.94 mL) was added, and the mixture was stirred at room temperature for 4 days. The reaction mixture was poured into water and extracted with diethyl ether. The extract was washed successively with 1 mol / L aqueous sodium hydroxide solution, water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (39 mL), n-butyllithium (2.64 mol / Ln-hexane solution, 3.25 mL) was added at −78 ° C., and the mixture was stirred at the same temperature for 30 min. Dry ice (10 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was acidified with 2 mol / L hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 2,3-difluoro-6- (2-methoxyethoxy) benzoic acid (1.48 g). The obtained 2,3-difluoro-6- (2-methoxyethoxy) benzoic acid (0.5 g) was dissolved in 1,4-dioxane (10 mL), and triethylamine (0.45 mL) and diphenylphosphoryl azide (0. 61 mL) was added and stirred overnight at room temperature. Ethanol (0.99 g) was added to the reaction mixture, and the mixture was heated to reflux for 5 hours. The reaction mixture was diluted with ethyl acetate, washed successively with 1 mol / L hydrochloric acid, water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. A 5 mol / L aqueous sodium hydroxide solution (4.3 mL) was added to a suspension of the residue in ethanol (10 mL), and the mixture was heated to reflux for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with water (twice) and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3/1) to obtain the title compound (75 mg).

Reference Example 333
The compound of Reference Example 333 described in Table 44 was obtained in the same manner as in Reference Example 332 using the corresponding starting materials.

Reference Example 334
2-Fluoro-5- [N- (2,6-difluorophenyl) -N-methylamino] methyl-4-methoxyaniline 4-fluoro-2-methoxy-5-nitrobenzyl alcohol (0.3 g) in methylene chloride (5 mL) To the solution, triethylamine (0.31 mL) and methanesulfonyl chloride (0.14 mL) were added at room temperature, and the mixture was stirred for 3 hours. The reaction mixture was diluted with methylene chloride, washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in acetonitrile (2 mL) -ethanol (2 mL), catalytic amounts of sodium iodide and 2,6-difluoroaniline (0.45 mL) were added, and the mixture was stirred at 60 ° C. overnight. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane to n-hexane / ethyl acetate = 2/3) to give 5-fluoro-2- [N- (2,6-difluorophenyl) amino] methyl. -4-Nitroanisole (0.41 g) was obtained. This was dissolved in N, N-dimethylformamide (3 mL), sodium hydride (55%, 84 mg) was added under ice cooling, and the mixture was stirred at the same temperature for 5 min. Methyl iodide (0.096 mL) was added to the reaction mixture, and the mixture was stirred overnight at room temperature. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane to n-hexane / ethyl acetate = 1/1) to give 5-fluoro-2- [N- (2,6-difluorophenyl) -N- Methylamino] methyl-4-nitroanisole (0.17 g) was obtained. This was dissolved in methanol (3 mL) -tetrahydrofuran (3 mL). Under ice cooling, nickel (II) bromide (5 mg) and sodium borohydride (52 mg) were added, and the mixture was stirred at the same temperature for 15 minutes and at room temperature for 15 minutes. did. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane to n-hexane / ethyl acetate = 3/2) to obtain the title compound (0.12 g).

Reference Example 335
The compound of Reference Example 335 described in Table 44 was obtained in the same manner as in Reference Example 334 using the corresponding starting materials.

Reference Example 336
2-Fluoro-5- [N- (2-fluoro-6-methoxyphenyl) -N-methylamino] methylaniline To a solution of 4-fluoro-3-nitrobenzoic acid (1.57 g) in methylene chloride (25 mL) was added N. , N-dimethylformamide (0.005 mL) and oxalyl chloride (4.32 g) were added, and the mixture was stirred at room temperature for 1 hour, and then the reaction mixture was concentrated under reduced pressure. A solution of the residue in tetrahydrofuran (5 mL) was added to a suspension of 2-fluoro-6-methoxyaniline (1.2 g) and sodium hydrogen carbonate (2.14 g) in tetrahydrofuran (10 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed successively with 1 mol / L hydrochloric acid, water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was suspended in methylene chloride, collected by filtration, and dried under reduced pressure to give 4-fluoro-3-nitro-N- (2-fluoro-6-methoxyphenyl) benzamide (1.1 g). This was dissolved in N, N-dimethylformamide (12 mL), sodium hydride (55%, 172 mg) and methyl iodide (0.76 g) were added under ice cooling, and the mixture was stirred overnight at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water (3 times) and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 4-fluoro-3-nitro-N- (2-fluoro-6-methoxyphenyl). ) -N-methylbenzamide (1.15 g) was obtained. The obtained 4-fluoro-3-nitro-N- (2-fluoro-6-methoxyphenyl) -N-methylbenzamide (0.3 g) was dissolved in methanol (10 mL) -tetrahydrofuran (10 mL), and ice-cooled. Nickel (II) bromide (10 mg) and sodium borohydride (0.11 g) were added, and the mixture was stirred at the same temperature for 30 minutes and at room temperature for 30 minutes. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 3-amino-4-fluoro-N- (2-fluoro-6-methoxyphenyl) -N. -Methylbenzamide (0.27 g) was obtained. This was dissolved in tetrahydrofuran (8 mL), borane-tetrahydrofuran complex (1 mol / L tetrahydrofuran solution, 3.3 mL) was added, and the mixture was heated to reflux for 2 hours. Methanol was added to the reaction mixture under ice cooling, and the mixture was stirred for 10 minutes. The mixture was poured into saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3/1) to obtain the title compound (0.11 g).

Reference examples 337-340
The compounds of Reference Examples 337 to 340 described in Table 45 were obtained in the same manner as in Reference Example 336 using the corresponding starting materials.

Reference examples 341 to 342
The compounds of Reference Examples 341 to 342 described in Table 45 were obtained in the same manner as in Reference Example 325 using the corresponding starting materials.

Reference examples 343 to 344
Instead of 4-fluoro-3-nitrophenol, 2,3-difluoro-6- (2-ethoxyethoxy) phenol or 2,3-difluoro-6- [2- (tert-butyldimethylsilyloxy) ethoxy] phenol is used. In the same manner as in Reference Example 21 except that 4-fluoro-3-nitrobenzyl alcohol was used instead of 1- (2-fluoro-6-methoxyphenyl) ethanol, Reference Examples 343 to 344 described in Table 45 were used. A compound was obtained.

Reference Example 345
4-Fluoro-3-nitro-2-methoxybenzoic acid Concentrated sulfuric acid (6 mL) was added to 4-fluoro-2-methoxybenzoic acid (0.96 g) under ice cooling, and the mixture was stirred for 15 minutes. Concentrated nitric acid (0.6 mL) was added to the mixture under ice cooling, and the mixture was stirred at the same temperature for 1 hour. Ice was added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes and extracted with ethyl acetate. The extract was washed with water (twice) and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. A mixed solvent (n-hexane / ethyl acetate = 2/1) was added to the residue, and the insoluble material was collected by filtration and dried under reduced pressure to obtain the title compound (0.78 g).

Reference Example 346
The compound of Reference Example 346 described in Table 46 was obtained in the same manner as in Reference Example 336 using the corresponding starting materials.

Example 1
5-Methoxycarbonyl-3- [2-chloro-5- (3,4-dihydroquinolin-1 (2H) -ylsulfonyl) phenyl] thieno [3,4-d] pyrimidine-2,4 (1H, 3H) -A solution of triphosgene (0.41 g) in tetrahydrofuran (5 mL) was added to a suspension of dione 4-aminothiophene-2,3-dicarboxylic acid dimethyl hydrochloride (0.5 g) and triethylamine (0.84 mL) in tetrahydrofuran (10 mL). In addition, the mixture was stirred at 60 ° C for 1 hour. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (8 mL) and 2-chloro-5- (3,4-dihydroquinolin-1 (2H) -ylsulfonyl) aniline (0.64 g) and 4-dimethylaminopyridine (0.49 g) were dissolved. The solution was added to a tetrahydrofuran (8 mL) solution and stirred at 60 ° C. for 2 hours. The reaction mixture was diluted with ethyl acetate, washed successively with 1 mol / L hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was dissolved in methanol (15 mL). To this solution was added sodium methoxide (28% methanol solution 1.15 mL), and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was diluted with ethyl acetate, washed successively with 1 mol / L hydrochloric acid, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 1/1) to obtain the title compound (0.65 g).

Examples 2 to 21
The compounds of Examples 2 to 21 listed in Tables 47 to 49 were obtained in the same manner as in Example 1 using the corresponding starting materials. However, in Example 6, ethanol was used instead of methanol, and sodium ethoxide was used instead of sodium methoxide.

Example 22
5-carboxy-3- [2-chloro-5- (3,4-dihydroquinolin-1 (2H) -ylsulfonyl) phenyl] thieno [3,4-d] pyrimidine-2,4 (1H, 3H)- Dione 5-methoxycarbonyl-3- [2-chloro-5- (3,4-dihydroquinolin-1 (2H) -ylsulfonyl) phenyl] thieno [3,4-d] pyrimidine-2,4 (1H, 3H Lithium hydroxide monohydrate (0.16 g) was added to a methanol (12 mL) -tetrahydrofuran (4 mL) solution of) -dione (0.2 g), and the mixture was stirred at 60 ° C. overnight. 1 mol / L hydrochloric acid was added to the reaction mixture, and the precipitated crystals were collected by filtration, washed with water and dried under reduced pressure to obtain the title compound (0.18 g).

Examples 23-29
The compounds of Examples 23 to 29 described in Tables 50 to 51 were obtained in the same manner as in Example 1 and Example 22 using the corresponding starting materials.

Example 30
5-carbamoyl-3- [2-chloro-5- (3,4-dihydroquinolin-1 (2H) -ylsulfonyl) phenyl] thieno [3,4-d] pyrimidine-2,4 (1H, 3H)- Dione 5-carboxy-3- [2-chloro-5- (3,4-dihydroquinolin-1 (2H) -ylsulfonyl) phenyl] thieno [3,4-d] pyrimidine-2,4 (1H, 3H) 1,1′-carbonylbis-1H-imidazole (9 mg) was added to a solution of dione (14 mg) in tetrahydrofuran (1 mL), and the mixture was stirred at room temperature for 1 hour. 28% aqueous ammonia (0.5 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: methylene chloride / methanol = 10/1) to obtain the title compound (13 mg).

Example 31
5-Methylcarbamoyl-3- [2-chloro-5- (3,4-dihydroquinolin-1 (2H) -ylsulfonyl) phenyl] thieno [3,4-d] pyrimidine-2,4 (1H, 3H) -Dione The title compound was obtained in the same manner as in Example 30 using the corresponding starting material.

Example 32
5- (1-hydroxy-1-methylethyl) -3- [2-chloro-5- (3,4-dihydroquinolin-1 (2H) -ylsulfonyl) phenyl] thieno [3,4-d] pyrimidine- 2,4 (1H, 3H) -dione 5-methoxycarbonyl-3- [2-chloro-5- (3,4-dihydroquinolin-1 (2H) -ylsulfonyl) phenyl] thieno [3,4-d] To a solution of pyrimidine-2,4 (1H, 3H) -dione (0.1 g) in tetrahydrofuran (10 mL) was added methylmagnesium iodide (3 mol / L diethyl ether solution, 0.19 mL) under ice-cooling, and overnight at room temperature. Stir. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 1/1) to obtain the title compound (85 mg).

Example 33
5-hydroxymethyl-3- [2-chloro-5- (3,4-dihydroquinolin-1 (2H) -ylsulfonyl) phenyl] thieno [3,4-d] pyrimidine-2,4 (1H, 3H) -Dione 5-methoxycarbonyl-3- [2-chloro-5- (3,4-dihydroquinolin-1 (2H) -ylsulfonyl) phenyl] thieno [3,4-d] pyrimidine-2,4 (1H, To a solution of 3H) -dione (0.2 g) in tetrahydrofuran (4 mL) was added diisobutylaluminum hydride (1.01 mol / L toluene solution, 1.5 mL) under ice cooling, and the mixture was stirred for 1 hour. Ethyl acetate was added to the reaction mixture, stirred for 10 minutes, 1 mol / L hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 1/1) to obtain the title compound (0.11 g).

Example 34
5-Formyl-3- [2-chloro-5- (3,4-dihydroquinolin-1 (2H) -ylsulfonyl) phenyl] thieno [3,4-d] pyrimidine-2,4 (1H, 3H)- Dione 5-hydroxymethyl-3- [2-chloro-5- (3,4-dihydroquinolin-1 (2H) -ylsulfonyl) phenyl] thieno [3,4-d] pyrimidine-2,4 (1H, 3H ) -Dione (77 mg) in N, N-dimethylformamide (2.1 mL) was added with manganese dioxide (IV) (0.77 g) and stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, and the insoluble material was removed by filtration. The filtrate was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 1/1) to obtain the title compound (32 mg).

Example 35
5-methoxycarbonyl-3- {2-fluoro-5- [1- (2-fluoro-6-methoxyphenyl) ethoxy] phenyl} thieno [3,4-d] pyrimidine-2,4 (1H, 3H)- To a mixture of dione 4-aminothiophene-2,3-dicarboxylic acid dimethyl hydrochloride (90 mg) and triethylamine (0.15 mL) in tetrahydrofuran (3 mL) was added a solution of triphosgene (74 mg) in tetrahydrofuran (3 mL) at 60 ° C. for 30 minutes. Stir. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (3 mL) and 2-fluoro-5- [1- (2-fluoro-6-methoxyphenyl) ethoxy] aniline (0.1 g) and 4-dimethylaminopyridine (88 mg) in tetrahydrofuran (3 mL). ) Added to solution and stirred at 60 ° C. overnight. 1 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was dissolved in methanol (5 mL). Sodium methoxide (28% methanol solution, 0.21 mL) was added to this solution, and the mixture was stirred at room temperature for 15 minutes. 1 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 1/2) to obtain the title compound (0.14 g).

Examples 36-47
The compounds of Examples 36 to 47 listed in Tables 52 to 53 were obtained in the same manner as in Example 35 using the corresponding starting materials.

Example 48
5-carboxy-3- {2-fluoro-5- [1- (2-fluoro-6-methoxyphenyl) ethoxy] phenyl} thieno [3,4-d] pyrimidine-2,4 (1H, 3H) -dione 5-methoxycarbonyl-3- {2-fluoro-5- [1- (2-fluoro-6-methoxyphenyl) ethoxy] phenyl} thieno [3,4-d] pyrimidine-2,4 (1H, 3H)- Lithium hydroxide monohydrate (99 mg) was added to a mixture of dione (0.12 g) and methanol (3 mL), and the mixture was stirred at 50 ° C. for 1 hr. The reaction mixture was acidified with 1 mol / L hydrochloric acid, and the precipitated crystals were collected by filtration, washed with water and dried under reduced pressure to give the title compound (0.11 g).

Examples 49-60
The compounds of Examples 49-60 shown in Tables 53-55 were obtained in the same manner as in Example 48 using the corresponding starting materials.

Examples 61-65
The compounds of Examples 61 to 65 shown in Table 55 were obtained in the same manner as in Example 35 using the corresponding starting materials.

Examples 66-70
The compounds of Examples 66 to 70 listed in Tables 55 to 56 were obtained in the same manner as in Example 48 or Example 93 using the corresponding starting materials.

Example 71
The compound of Example 71 described in Table 56 was obtained in the same manner as in Example 35 using the corresponding starting materials.

Example 72
5-methoxycarbonyl-3- [3- (1-phenylethylsulfinyl) phenyl] thieno [3,4-d] pyrimidine-2,4 (1H, 3H) -dione 5-methoxycarbonyl-3- [3- ( 1-phenylethylthio) phenyl] thieno [3,4-d] pyrimidine-2,4 (1H, 3H) -dione (50 mg) in acetone (3 mL) -water (0.6 mL) solution in sodium bicarbonate (24 mg ) And OXONE® (84 mg) were added and stirred at room temperature for 30 minutes. The reaction mixture was extracted with ethyl acetate, the extract was washed successively with 1 mol / L hydrochloric acid, water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was suspended in methanol, collected by filtration and dried under reduced pressure to obtain the title compound (45 mg).

Example 73
5-methoxycarbonyl-3- [3- (1-phenylethylsulfonyl) phenyl] thieno [3,4-d] pyrimidine-2,4 (1H, 3H) -dione 5-methoxycarbonyl-3- [3- ( 1-phenylethylthio) phenyl] thieno [3,4-d] pyrimidine-2,4 (1H, 3H) -dione (50 mg) in acetone (3 mL) -water (0.6 mL) in sodium bicarbonate (77 mg) ) And OXONE® (0.28 g) were added and stirred at room temperature for 30 minutes. The reaction mixture was extracted with ethyl acetate, the extract was washed successively with 1 mol / L hydrochloric acid, water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was suspended in methanol, collected by filtration, and dried under reduced pressure to obtain the title compound (48 mg).

Examples 74-76
The compounds of Examples 74 to 76 listed in Tables 56 to 57 were obtained in the same manner as in Example 35 using the corresponding starting materials.

Example 77
The compound of Example 77 described in Table 57 was obtained in the same manner as in Example 73 using the corresponding starting materials.

Example 78
The compound of Example 78 described in Table 57 was obtained in the same manner as in Example 35 using the corresponding starting materials.

Examples 79-82
The compounds of Examples 79 to 82 described in Table 57 were obtained in the same manner as in Example 48 using the corresponding starting materials.

Example 83
The compound of Example 83 described in Table 58 was obtained in the same manner as in Example 73 and Example 48 using the corresponding starting materials.

Examples 84-87
The compounds of Examples 84 to 87 described in Table 58 were obtained in the same manner as in Example 48 using the corresponding starting materials.

Example 88
The compound of Example 88 described in Table 58 was obtained in the same manner as in Example 73 and Example 48 using the corresponding starting materials.

Examples 89-92
The compounds of Examples 89 to 92 described in Tables 58 to 59 were obtained in the same manner as in Example 35 using the corresponding starting materials.

Example 93
5-carboxy-3- [2-fluoro-5- (N-methyl-N-phenylcarbamoyl) phenyl] thieno [3,4-d] pyrimidine-2,4 (1H, 3H) -dione 5-methoxycarbonyl- 3- [2-Fluoro-5- (N-methyl-N-phenylcarbamoyl) phenyl] thieno [3,4-d] pyrimidine-2,4 (1H, 3H) -dione (0.18 g) and lithium hydroxide A mixture of monohydrate (0.17 g) in tetrahydrofuran (6 mL) -methanol (3 mL) -water (3 mL) was stirred at room temperature for 2 hours. The reaction mixture was poured into 1 mol / L hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: methylene chloride / methanol = 8/1) to obtain the title compound (0.12 g).

Example 94
The compound of Example 94 described in Table 59 was obtained in the same manner as in Example 35 and Example 93 using the corresponding starting materials.

Examples 95-97
The compounds of Examples 95 to 97 listed in Table 59 were obtained in the same manner as in Example 93 using the corresponding starting materials.

Examples 98-100
The compounds of Examples 98 to 100 listed in Tables 59 to 60 were obtained in the same manner as in Example 35 using the corresponding starting materials.

Examples 101-103
The compounds of Examples 101 to 103 listed in Table 60 were obtained in the same manner as in Example 48 using the corresponding starting materials.

Examples 104-108
The compounds of Examples 104 to 108 listed in Table 61 were obtained in the same manner as in Example 1 using the corresponding starting materials.

Examples 109-201
The compounds of Examples 109 to 201 listed in Tables 61 to 74 were obtained in the same manner as in Example 1, Example 48, or Example 93 using the corresponding starting materials.

Example 202
5-carboxy-3- [2-fluoro-5- (1-methyl-1-phenylethylsulfonyl) phenyl] thieno [3,4-d] pyrimidine-2,4 (1H, 3H) -dione 2-fluoro- In the same manner as in Example 35, using 2-fluoro-5- (1-methyl-1-phenylethylthio) aniline instead of 5- [1- (2-fluoro-6-methoxyphenyl) ethoxy] aniline. Obtained 5-methoxycarbonyl-3- [2-fluoro-5- (1-methyl-1-phenylethylthio) phenyl] thieno [3,4-d] pyrimidine-2,4 (1H, 3H) -dione ( 0.1 g) was dissolved in methylene chloride (2 mL), 3-chloroperbenzoic acid (92 mg) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, 1 mol / L aqueous sodium thiosulfate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1/1 to 1/2) to give 5-methoxycarbonyl-3- [2-fluoro-5- (1-methyl-1). -Phenylethylsulfonyl) phenyl] thieno [3,4-d] pyrimidine-2,4 (1H, 3H) -dione (0.1 g) was obtained. Obtained instead of 5-methoxycarbonyl-3- [2-fluoro-5- (N-methyl-N-phenylcarbamoyl) phenyl] thieno [3,4-d] pyrimidine-2,4 (1H, 3H) -dione 5-methoxycarbonyl-3- [2-fluoro-5- (1-methyl-1-phenylethylsulfonyl) phenyl] thieno [3,4-d] pyrimidine-2,4 (1H, 3H) -dione And the title compound was obtained in the same manner as in Example 93.

Examples 203-232
The compounds of Examples 203 to 232 described in Tables 75 to 79 were obtained in the same manner as in Example 202 using the corresponding starting materials.

Example 233
5-carboxy-3- [2-fluoro-5- (2,3-difluoro-6-methoxybenzyloxy) -4-methoxyphenyl] thieno [3,4-d] pyrimidine-2,4 (1H, 3H) To a suspension of dione 4-aminothiophene-2,3-dicarboxylic acid dimethyl hydrochloride (0.13 g) and triethylamine (0.21 mL) in tetrahydrofuran (5 mL) was added triphosgene (99 mg) under ice-cooling, and For 30 minutes. The reaction mixture was diluted with ethyl acetate, insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (4 mL) and 2-fluoro-5- (2,3-difluoro-6-methoxybenzyloxy) -4-methoxyaniline (0.16 g) and 4-dimethylaminopyridine (0.12 g). In tetrahydrofuran (4 mL) and stirred at 60 ° C. for 3 days. The reaction mixture was passed through Isoroute SCX manufactured by IST and eluted with ethyl acetate. The eluate was concentrated under reduced pressure, the residue was dissolved in methanol (5 mL), sodium methoxide (28% methanol solution, 0.29 mL) was added, and the mixture was stirred at room temperature for 30 min. 1 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. A mixture of the residue and lithium hydroxide monohydrate (0.21 g) in tetrahydrofuran (4 mL) -methanol (2 mL) -water (2 mL) was stirred at room temperature for 30 minutes. The reaction mixture was poured into 1 mol / L hydrochloric acid and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 2-ethyl acetate) to obtain the title compound (0.13 g).

Examples 234-391
The compounds of Examples 234 to 391 listed in Tables 79 to 102 were obtained in the same manner as in Example 233 using the corresponding starting materials.

Example 392
The compound of Example 392 described in Table 102 was obtained in the same manner as in Example 35 and Example 33 using the corresponding starting materials.

Examples 393-395
The compounds of Examples 393 to 395 described in Table 102 were obtained in the same manner as in Example 30 using the corresponding starting materials.

Example 396
5-carboxy-3- {2-fluoro-5- [2,3-difluoro-6- (2-hydroxyethoxy) benzyloxy] phenyl} thieno [3,4-d] pyrimidine-2,4 (1H, 3H ) -Dione To a suspension of 4-aminothiophene-2,3-dicarboxylic acid dimethyl hydrochloride (0.11 g) and triethylamine (0.19 mL) in tetrahydrofuran (5 mL), triphosgene (84 mg) was added under ice-cooling. Stir at 30 ° C. for 30 minutes. The reaction mixture was diluted with ethyl acetate, insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (4 mL) and 2-fluoro-5- {2,3-difluoro-6- [2- (tert-butyldimethylsilyloxy) ethoxy] benzyloxy} aniline (0.17 g) and 4- To a solution of dimethylaminopyridine (99 mg) in tetrahydrofuran (4 mL), the mixture was stirred at 60 ° C. overnight. The reaction mixture was passed through Isoroute SCX manufactured by IST and eluted with ethyl acetate. The eluate was concentrated under reduced pressure, the residue was dissolved in methanol (4 mL), sodium methoxide (28% methanol solution, 0.23 mL) was added, and the mixture was stirred at room temperature for 30 min. 1 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (4 mL), tetra (n-butyl) ammonium fluoride (1 mol / L tetrahydrofuran solution, 1.2 mL) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was poured into 1 mol / L hydrochloric acid and extracted with ethyl acetate. The extract was washed successively with 1 mol / L hydrochloric acid, water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. A mixture of the residue and lithium hydroxide monohydrate (0.17 g) in tetrahydrofuran (5 mL) -methanol (2.5 mL) -water (2.5 mL) was stirred at room temperature for 30 minutes. 1 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to obtain the title compound (0.13 g).

Examples 397-410
The compounds of Examples 397 to 410 listed in Tables 102 to 104 were obtained in the same manner as in Example 396 using the corresponding starting materials.

Examples 411-416
The compounds of Examples 411 to 416 described in Tables 104 to 105 were obtained in the same manner as in Example 233 using the corresponding starting materials.

Example 417
5-Ethoxycarbonyl-3- {2-fluoro-5- [2,3-difluoro-6- (2-hydroxyethoxy) benzyloxy] phenyl} thieno [3,4-d] pyrimidine-2,4 (1H, 3H) -dione 5-carboxy-3- {2-fluoro-5- [2,3-difluoro-6- (2-hydroxyethoxy) benzyloxy] phenyl} thieno [3,4-d] pyrimidine-2,4 P-Toluenesulfonic acid monohydrate (24 mg) was added to a suspension of (1H, 3H) -dione (0.65 g) in ethanol (10 mL) -tetrahydrofuran (5 mL) and stirred overnight at an external temperature of 90 ° C. did. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 1/2 to 1/4) to obtain the title compound (0.39 g).

Example 418
5-ethoxycarbonyl-3- (5- {6- [2- (ethoxycarbonyloxy) ethoxy] -2,3-difluorobenzyloxy} -2-fluorophenyl) thieno [3,4-d] pyrimidine-2, 4 (1H, 3H) -dione 5-ethoxycarbonyl-3- {2-fluoro-5- [2,3-difluoro-6- (2-hydroxyethoxy) benzyloxy] phenyl} thieno [3,4-d] To a suspension of pyrimidine-2,4 (1H, 3H) -dione (80 mg) in ethyl acetate (2 mL) were added pyridine (0.036 mL) and ethyl chloroformate (0.021 mL), and the mixture was stirred overnight at room temperature. . The reaction mixture was poured into 1 mol / L hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1/2) to give the title compound (38 mg).

Example 419
The compound of Example 419 described in Table 106 was obtained in the same manner as in Example 418 using the corresponding starting materials.

Examples 420-426
The compounds of Examples 420 to 426 described in Tables 106 to 107 were obtained in the same manner as in Example 233 using the corresponding starting materials.

Example 427
The compound of Example 427 described in Table 107 was obtained in the same manner as in Example 396 using the corresponding starting materials.

Example 428
The compound of Example 428 described in Table 107 was obtained in the same manner as in Example 233 using the corresponding starting materials.

The chemical structures and ¹ H-NMR data of the reference compounds ¹ to 346 are shown in Tables ^{1 to} 46, and the chemical structures and ¹ H-NMR data of the example compounds ¹ to 428 are shown in Tables 47 to 107, respectively.

The abbreviations in the table are Ref No. Is Reference Example Number, Ex No. Represents an example number, Strc represents a chemical structural formula, and Solv represents a ¹ H-NMR measurement solvent.

[Test Example 1]
1) Cloning of human GnRH receptor 1 (GnRHR1) and recombinant human pituitary-derived cDNA (Becton Dickinson) into an expression vector, template No. 45 of human GnRHR1 (Accession No. L03380) reported by Kakar et al. To 1115 was amplified by PCR and inserted into the multiple cloning site of pcDNA3.1 (+) (Invitrogen). The nucleotide sequence of the inserted DNA was completely identical to the reported nucleotide sequence.

2) Preparation of human GnRH receptor 1-expressing HEK293 (human fetal kidney) cells Introduction of human GnRHR1 gene into HEK293 cells cultured (medium: MEM, 10% FCS, antibiotics, non-essential amino acids, pyruvate) The obtained expression vector was introduced by a lipofection method using Lipofectamine 2000 (Invitrogen). After introduction, the cells were cultured for 2 days and used for experiments.

3) Measurement of GnRH antagonistic effect The antagonistic action of a compound on human GnRHR1 was evaluated by changes in intracellular calcium concentration by GnRH stimulation. For HEK293 cells that transiently expressed GnRHR1, the medium was removed, and 200 μL of washing buffer (Hanks' Balanced Salt Solutions, 20 mM N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid per well) , 1.3 mM calcium chloride, 0.5 mM magnesium chloride, 0.4 mM magnesium sulfate). 100 μL of a dye solution that reacts with calcium ions (FLIPR Calcium Assay Kit, manufactured by Molecular Devices) was added and incubated at 37 ° C. with 5% CO _{2 for} 1 hour. Thereafter, the intracellular calcium concentration was measured using FLEX STATION (Molecular Device) under the following conditions. 50 μL of a test substance diluted with a measurement buffer (washing buffer containing 0.1% fetal bovine serum albumin) was added in a chamber heated to 37 ° C., and 1 μm after that, 50 μL of 5 nM GnRH was added. . The concentration (IC ₅₀ value) that inhibits intracellular calcium movement by GnRH stimulation by 50% was calculated by logit plot (Table 108).

[Test Example 2] Oral absorbability confirmation test
1) Preparation of specimen for measuring drug concentration by intravenous administration in the tail vein SD rats (Charles River, male 7 weeks old, 170-210 g) fasted overnight were used as experimental animals. To 1 mg of the test compound, 0.2 mL of N, N-dimethylacetamide, 0.798 mL of physiological saline, and 0.002 mL of 2N NaOH were added and dissolved to prepare a 1.0 mg / mL solution. Rats were weighed and the test compound was administered intravenously in the tail vein under anesthesia at a dose of 1 mL / kg (1 mg / kg). Caudal vein administration was performed using a 26G needle and a 1 mL syringe. Blood collection times were 2, 15, 60, 120, 240 and 360 minutes after tail vein administration. Blood was centrifuged, and plasma was used as a sample for measuring blood drug concentration.

2) Preparation of specimen for measuring drug concentration by oral administration SD rats (Charles River, male 7 weeks old, 170-210 g) fasted overnight were used as experimental animals. To 3 mg of the test compound, N, N-dimethylacetamide 0.2 mL, 0.5% sodium methylcellulose aqueous solution 9.794 mL, and 2N NaOH 0.006 mL were added and dissolved to prepare a 0.3 mg / mL solution. . Rats were weighed and test compounds were orally administered at a dose of 10 mL / kg (3 mg / kg). Oral administration was performed using a rat sonde and a 2.5 mL syringe. The blood collection time was 15, 30, 60, 120, 240 and 360 minutes after oral administration. Blood was centrifuged, and plasma was used as a sample for measuring blood drug concentration.

3) Measurement of drug concentration After 0.1 mL of an appropriate internal standard substance was added to 0.025 mL of the plasma obtained in 1) and 2) according to a conventional method, 0.875 mL of acetonitrile was added to perform protein removal. After centrifugation, 0.005 mL of the supernatant was injected into LC-MS / MS. The blood drug concentration was measured by the LC-MS / MS method under the following conditions. A calibration curve was prepared by appropriately adding an internal standard substance and various compounds to be measured to 0.05 mL of blank plasma according to a conventional method and operating in the same manner as described above.
LC
Device: Agilent 1100
Column: Cadenza C18 3 μm 4.6 × 50 mm
Mobile phase: 10 mM ammonium acetate aqueous solution (pH 4.5) (A) / acetonitrile (B) (Times and ratios of (A) and (B) are shown in Table 109.)
Column temperature: 40 ° C
Flow rate: 0.5 mL / min
MS / MS
Device: API-4000
Ionization method: ESI (Turbo Ion Spray)

The bioavailability (%) is determined based on the blood drug concentration by the tail vein administration and oral administration of the test compound using the WinNon Professional from Pharsight Corporation, based on the blood drug concentration obtained by the above method. The area under the curve was calculated and calculated based on the following formula.
Bioavailability (%) = {[(Blood drug concentration after oral administration-Area under time curve) / 3] / (Blood drug concentration after tail vein administration-Area under time curve)} × 100
Tables 110 to 112 show the maximum blood drug concentration (Cmax), bioavailability, and blood drug concentration 360 minutes after administration (C ₃₆₀ ) at the time of oral administration, respectively.

  In Tables 110 to 112, Control Compound 1 is the sulfonamide compound of Example 6 (4) described in Patent Document 2, and Control Compound 2 is the sulfonamide compound of Example 31 described in Patent Document 2. .

  As a result, the fused heterocyclic derivative of the present invention is superior in blood kinetics (blood transferability, sustainability) by oral administration compared to the control compound. For example, the condensed heterocyclic derivatives of Examples 48, 146, 191, 202, 233, 271, 367, 414, 420 are more effective than the compound having the sulfonamide group of Example 22 and the compound having the amide group of Example 95. Further, it is excellent in blood transferability, and is more preferable as a pharmaceutical composition for oral administration. In addition, the fused heterocyclic derivatives of Examples 146, 202, 233, 271, 367, 414, 420 (more preferably Examples 146, 233, 271, 367, 414) were administered after oral administration compared to the control compound. The drug concentration in blood for 6 hours was maintained, and the durability was excellent. Therefore, the condensed heterocyclic derivative of the present invention can be made into a sustained-release preparation substantially free from sustained-release bases such as hydroxyalkyl cellulose and alkyl cellulose.

  Since the fused heterocyclic derivative (I) or a prodrug thereof or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof according to the present invention has an excellent GnRH antagonistic action, gonadotropin release It can be used as a prophylactic or therapeutic agent for sex hormone-dependent diseases by regulating the action of hormones and controlling production and secretion of gonadotropins and sex hormones. Therefore, according to the present invention, prostatic hypertrophy, uterine fibroids, endometriosis, uterine fibroma, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, polycystic ovary syndrome, lupus erythematosus, Hirsutism, dwarfism, sleep disorders, acne, baldness, Alzheimer's disease, infertility, irritable bowel syndrome, prostate cancer, uterine cancer, ovarian cancer, breast cancer or pituitary tumor preventive or therapeutic agent, reproductive regulator, A contraceptive, an ovulation inducing agent, a sex hormone-dependent cancer postoperative recurrence preventive agent, or the like can be provided.

Claims (7)

5-carboxy-3- {2-fluoro-5- [1- (2-fluoro-6-methoxyphenyl) ethoxy] phenyl} thieno [3,4-d] pyrimidine-2,4 (1H, 3H) -dione ,
5-carboxy-3- [2-fluoro-5- (2,3-difluoro-6-methoxybenzyloxy) -4-methoxyphenyl] thieno [3,4-d] pyrimidine-2,4 (1H, 3H) -Dione,
5-carboxy-3- [2-chloro-5- (1-methyl-1-phenylethoxy) phenyl] thieno [3,4-d] pyrimidine-2,4 (1H, 3H) -dione, and
5-carboxy-3- {2-fluoro-5- [2,3-difluoro-6- (2-methoxyethoxy) benzyloxy] phenyl} thieno [3,4-d] pyrimidine-2,4 (1H, 3H ) -Dione
Condensed heterocyclic inducing member or the drug is selected from pharmacologically acceptable salt, or hydrate or solvate thereof. 5-carboxy-3- {2-fluoro-5- [1- (2-fluoro-6-methoxyphenyl) ethoxy] phenyl} thieno [3,4-d] pyrimidine-2,4 (1H, 3H) -dione in it, according to claim 1 fused heterocyclic inducing member or a pharmacologically acceptable salt thereof according, or a hydrate or solvate thereof. 5-carboxy-3- [2-fluoro-5- (2,3-difluoro-6-methoxybenzyloxy) -4-methoxyphenyl] thieno [3,4-d] pyrimidine-2,4 (1H, 3H) - a dione, according to claim 1 fused heterocyclic inducing member or a pharmacologically acceptable salt thereof according, or a hydrate or solvate thereof. 5. Carboxy-3- [2-chloro-5- (1-methyl-1-phenylethoxy) phenyl] thieno [3,4-d] pyrimidine-2,4 (1H, 3H) -dione. 1 fused heterocyclic inducing member or a pharmacologically acceptable salt thereof according, or a hydrate or solvate thereof. 5-carboxy-3- {2-fluoro-5- [2,3-difluoro-6- (2-methoxyethoxy) benzyloxy] phenyl} thieno [3,4-d] pyrimidine-2,4 (1H, 3H ) - a-dione, according to claim 1 fused heterocyclic inducing member or a pharmacologically acceptable salt thereof according, or a hydrate or solvate thereof. Condensed heterocyclic inducing member or a pharmacologically acceptable salt thereof, or a pharmaceutical composition containing a hydrate or solvate thereof as an active ingredient according to any one of claims 1-5. 7. The pharmaceutical composition according to claim 6 , which is a gonadotropin releasing hormone antagonist.